Histone Deacetylase Inhibitors and Methods of Use Thereof

ABSTRACT

The present invention relates to methods of modulating activity of histone deacetylases (HDACs). The present invention also relates to methods of treating HDAC-associated diseases including, but not limited to, cancers, inflammatory disorders, and neurodegenerative disorders. The present invention also provides novel compounds and compositions thereof and methods of preparation of the same. The present invention also includes methods of inhibiting HDACs, and methods of treating HDAC-associated diseases using the compounds of the invention.

FIELD

Described herein are compounds as isoform selective histone deacetylaseinhibitors, their derivatives, analogs, tautomeric forms, isotope forms,stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates,solvates, pharmaceutical acceptable salts, metabolites, intermediatesand prodrugs thereof, the preparation of these compounds, thepharmaceutical compositions comprising these compounds and the use ofthese compounds for treating various diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationSer. No. 62/636,966, filed on Mar. 1, 2018 and 62/721,764, filed on Aug.23, 2018 which are incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

Histone deacetylases (HDACs) have emerged as pharmaceutical targets witha broad range of potential indications. Several pan-HDAC inhibitors (notparalogue selective) of different chemotypes, which target several ofthe 11 paralogues of Zn-dependent HDACs and span different chemotypes,are approved by the FDA or are currently in clinical trials. However,these nonselective agents typically lead to undesired side effects, andconsiderable efforts are still spent toward the development of moreselective chemical probes and drug candidates.

Histone deacetylase proteins are a family of enzymes that control theacetylation state of protein lysine residues, notably lysine residuescontained in the N-terminal extensions of core histones. The acetylationstate of histones affects gene expression by influencing chromatinconformation. In addition, the stability or biological function ofseveral non-histone proteins is regulated by the acetylation state ofspecific lysine residues (Gallinari et al., 2007, Cell Res. 17:191-211;Kazantsev and Thompson, 2008, Nat Rev Drug Discov. 7:854-868).

In humans, HDAC proteins comprise a family of 18 members, which areseparated into four classes based on size, cellular localization, numberof catalytic active sites, and homology to yeast HDAC proteins. Class Iincludes HDAC1, HDAC2, HDAC3, and HDAC8. Class I HDACs are ubiquitouslyexpressed, largely restricted to the nucleus and in the case of HDACs 1,2 and 3, known to deacetylate histones. They share a highly conservedand homologous N-terminal catalytic domain. Class II consists of sixHDAC proteins that are further divided into two subclasses. Class Haincludes HDAC4, HDAC5, HDAC7, and HDAC9, which each contain a singlecatalytic active site. Class Ha HDACs display more tissue specificdistribution and can translocate between the nucleus and cytoplasm.These enzymes display weak inherent catalytic activity and requirehigher order protein complexes, often containing HDAC3, to becomecatalytically competent deacetylases. Class lib includes HDAC6 andHDAC10, which each contain two active sites, although only HDAC6 has twocatalytically competent active sites. The Class lib HDACs include HDACs6 and 10 with HDAC6 being predominantly localized to the cytoplasm whilelittle is known about the localization of HDAC10. The Class lib HDACsuniquely contain two independently active and substrate specificcatalytic domains and it is the N-terminal domain of HDAC6 that isresponsible for the deacetylation of α-tubulin.

The Class IV HDAC is composed of a single enzyme, HDAC11, with littleknown about its function; however, it has been detected across a broadrange of tissue types including heart, muscle, kidney and testes. HDAC11is the sole member of class IV, based on phylogenetic analysis. Class I,II, and IV HDAC proteins operate by a metal ion-dependent mechanism, asindicated by crystallographic analysis. In contrast, class III HDACproteins, referred to as sirtuins (i.e., SIRT1 through SIRT7), operateby a NAD⁺-dependent mechanism unrelated to the other HDAC proteins(Gregoretti et al., 2004, J Mol Biol. 338:17-31; Grozinger andSchreiber, 2002, Chem Biol. 9:3-16).

Small molecules have been developed with varied inhibitory profiles fromseveral chemical classes including alkanoic acids (sodium butyrate[NaB]), hydroxamic acids (SAHA) and ortho-aminoanilides (MS-275). Thesecompounds are well established inhibitors of primarily the Class IHDACs, and have served as the pharmacological workhorses in clinical,(SAHA [Vorinostat™], MS-275 [Entinostat™] and valproate [Depakote™]) andpreclinical studies (vide infra). The majority of inhibitors arenonselective and inhibit multiple isoforms both within and acrossclasses. Although the alkanoic acids (NaB, phenyl butyrate andvalproate) have been used extensively as HDAC inhibitors, thesecompounds display weak inhibitory activity of the Class I HDACs. On thecontrary, hydroxamic acids and ortho-aminoanilides are potentinhibitors, and depending on substitution patterns, display Class I andII or sub-Class I selectivity, respectively.

The overexpression of different isoforms of HDACs has been found inseveral types of cancers, as well as in neurological and inflammatorypathologies. The use of HDAC inhibitors represents a treatment for suchdiseases (Valente and Mai, 2014, Expert Opin. Ther. Patents, 24:1-15;Falkenberg and Johnstone, 2014, Nat Rev Drug Discov. 13:673-91). Thefollowing are examples of HDAC inhibitors that have been tested inclinical trials both as single agents and in combination withchemotherapies and other targeted therapeutics: ACY1215 (Acetylon),CG200745 (Crystal Genomics), 4SC-202 (4SC corporation), CHR-2845 (ChromaTherapeutics), AR-42 (Amo Therapeutics), CUDC-101 (Curis Inc),Givinostat (Italfarmaco), Resminostat (4SC- Corporation), Pracinostat(S*BIO Pte Ltd), Etinostat (Syndax), Abexinostat (Pharmacydies),Mocetinostat (Methylgene), Belinostat (TopoTarget), Valproic Acid(Instituto Nacional de Cancerologia), Panobinostat (Novartis),Vorinostat (Merck), and Romidepsin (Celgene).

HDAC inhibitors have been combined with a broad range of agents (Bots, &Johnstone, 2009. Clin. Cancer Res. 15, 3970-3977; Mottamal et al, 2015,Molecules, 20, 3898-3941). The following are examples of drugs andtreatment that have been tested in combination with HDAC inhibitors:5-fluorouracil, Bortezomib, Carboplatin, Paclitaxel, Cisplatin,Cyclophosphamide, Doxorubicin, Hydroxycarbamide, Hydroxychloroquine,Leucovorin, Marizomib, Pazopanib, Sorafenib, Temozolomide, and radiationetc. The most prominent example of the empirical testing of HDACinhibitors in combination is with DNA-damaging chemotherapeutics, whichhave led to many successful outcomes (Thurn, et al, 2011, Future Oncol.7, 263-283). HDAC inhibitors have also been successfully combined withDNMT inhibitors. Two Phase I trials have been carried out withvorinostat and bortezomib for the treatment of relapsing and/orrefractory multiple myeloma with overall positive responses (Weber D M,Graef T et al 2012, Clin. Lymphoma Myeloma Leuk. 12, 319-324). A PhaseIII trial is currently assessing VP A (Valproic acid) in combinationwith levocamitine in children with spinal muscular atrophy(ClinicalTrials.gov identifier: NCT01671384). Vorinostat, panobinostatand VP A are currently being tested in combination with variousantiretroviral therapies (ClinicalTrials.gov identifiers: NCT01680094,NCT01319383 and NCT01365065). A Phase I study combining Panobinostatwith Ipilimumab to treat unresectable III/IV melanoma has just started(ClinicalTrials.gov identifiers: NCT02032810). HDAC6-specificinhibitors, rocilinostat (ACY-1215), is being tested clinically for thetreatment of multiple myeloma in combination with bortezomib, followingpromising preclinical results (Santo L, Hideshima T, et al, 2012,Blood.; 119: 2579-2589.).

Many of the earlier HDAC inhibitors tested in clinical trials are eitherpan-inhibitors or have poor isoform selectivity. Thus, there is aninterest in identifying HDAC inhibitors exhibiting selectivity within orbetween the human HDAC isoform classes. Achieving selectivity would notonly reduce side effects, but would also provide the ability to targetdistinct therapeutic areas (Hu et al., 2003, J Pharmacol. Ther. 307:720-728; Giannini et al., 2012, Future Med Chem. 4:1439-1460; Weïwer etal., 2013, Future Med Chem. 5:1491-1508; Falkenberg and Johnstone, 2014,Nat Rev Drug Discov. 13:673-91).

HDAC6 is a well-characterized class lib deacetylase that regulates manyimportant biological processes via the formation of complexes with itspartner proteins. HDAC6 possesses two catalytic domains and a C-terminalzinc finger domain (ZnF-UBP domain, also known as BUZ) that binds freeubiquitin, as well as mono and polyubiquitinated proteins, with highaffinity. HDAC6 is localized predominantly in the cytoplasm, and hasbeen reported as a tubulin deacetylase that has effects on microtubule(MT)-mediated processes through both deacetylase-dependent anddeacetylase-independent mechanisms. HDAC6 is important both forcytoplasmic and nuclear functions, including cell motility andcontrolling cytoskeletal dynamics. Unlike other deacetylases, HDAC6 hasunique substrate specificity for non-histone proteins such as α-tubulin,HSP90, cortactin, peroxiredoxins, chaperone proteins, β-Catenin, andhypoxia inducible factor-1α (HIF-1α) (Blackwell et al., 2008, LifeScience 82:1050-1058; Shnakar and Sirvastava, 2008, Adv Exp Med Biol615:261-298). HDAC6 also deacetylates protein peroxiredoxins, which areproteins critical in protecting cells from the oxidative effects of H₂O₂(Parmigiani et al., 2008, PNAS 105:9633-9638). However, HDAC6 does notcatalyze histone deacetylation in vivo. Therefore, it is a safer drugtarget since it does not impact DNA biology. As a MT-mediatedcytoplasmic enzyme, HDAC6, through complexes with partner proteins,regulates multiple important biological processes, such as cellmigration, cell spreading, immune synapse formation, viral infection,the degradation of misfolded proteins and stress granule (SG) formation.HDAC6 is a vital regulator for mitochondrial transport, inhibiting HDAC6promotes the mitochondrial dynamics in Aβ-treated neurons. InhibitingHDAC6 via deacetylating α-tubulin significantly restored the length ofthe mitochondria shortened by Aβ to a normal level and rescuedhippocampal neuron impairment induced by Aβ. Mice lacking HDAC6 areviable and have greatly elevated tubulin acetylation in multiple organs.In addition, mice lacking HDAC6 exhibit a moderately impaired immuneresponse and bone homeostasis. In addition, mice lacking HDAC6 exhibit amoderately impaired immune response and bone homeostasis. HDAC6selective inhibitors, Tubastatin A and Ricolinostat (ACY-1215), havedemonstrated the capability of improving microtubule stability andameliorate cognitive impairment in Alzheimer's diseases mouse bypromoting tubulin acetylation, reducing production of Aβ andhyper-phosphorylated tau and facilitating autophagic clearance of Aβ andhyper-phosphorylated tau. Compared to HDAC Pa-inhibitor, such as SAHA,HDAC6 selective inhibitors will have much less toxic effects, which isvery important especially for chronic indications. The current mostadvanced HDAC6 selective HDAC6 inhibitor is Ricolinostat, which has beenmultiple clinical trials. For example, as a mono agent and combinationagent with Bortezomib, Dexamethasone, Pomalidomide and Lenalidomiderespectively, Ricolinostat had clinical trials for Multiple Myeloma andin Relapsed-and-Refractory Multiple Myeloma, relapsed/refractoryLymphoid Malignancies; combination with BCR pathway Inhibitors forrelapsed chronic lymphocytic leukemia; combination with Nab-paclitaxelfor metastatic breast cancer etc. Such diverse functions of HDAC6suggest that HDAC6 serves a potential therapeutic target for thetreatment of a wide range of diseases. HDAC6 selective inhibitors havebeen tested in preclinical indications for cancers, neurology,inflammation, Gaucher's disease, Parkinson's disease, Huntington'sdisease; Alzheimer's diseases, depression and anxiety, and pain etc.(Gianniniet et al., 2012, Future Med Chem. 4:1439-1460; Falkenberg andJohnstone, 2014, Nat Rev Drug Discov. 13:673-91; Mottamal et al. 2015Molecules, 20:3898-3941; Yang et al. 2017 TranslationalNeurodegeneration, 6:19).

HDAC8, on the basis of sequence homology, is considered to be a class Ienzyme, although phylogenetic analysis has shown it to lay near theboundary of the class I and class II enzymes. HDAC8's importance hasbeen revealed by knockdown experiments of selective HDAC isoformsshowing it as essential for cell survival. HDAC8 specific inhibitionselectively induces apoptosis in T-cell derived lymphoma and leukemiccells. The expression of HDAC8 has been described in a variety of cancerentities e.g. colon, breast lung, pancreas and ovary cancer (Nakagawa etal. 2007, Oncol Rep, 18:769-774). In the highly malignant childhoodcancer neuroblastoma high HDAC8 expression significantly correlates withpoor prognostic markers and poor overall and event-free survival. Incultured neuroblastoma cells knockdown and pharmacological inhibition ofHDAC8 resulted in inhibition of proliferation, reduced clonogenicgrowth, cell cycle arrest and differentiation (Oehme et al. 2009, ClinCancer Res, 15:91-99). Furthermore, HDAC8 promotes lung, colon andcervical cancer cell proliferation and may regulate telomerase activity.The three dimensional crystal structure of human HDAC8 was the first tobe solved, and 14 human HDAC8 structures co-crystallized with differentinhibitors have been described. Currently, HDAC 8 selective inhibitorsare in preclinical trials for cancer (Giannini G et al., 2012, FutureMed Chem. 4:1439-1460; Falkenberg and Johnstone, 2014, Nat Rev DrugDiscov. 13:673-91).

Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes,which are dependent on NAD(+) for activity. Sirtuins activity is linkedto gene repression, metabolic control, apoptosis and cell survival, DNArepair, development, inflammation, neuroprotection, and healthy aging.Because sirtuins modulation could have beneficial effects on humandiseases there is a growing interest in the discovery of small moleculesmodifying their activities. Sirtuin inhibitors with a wide range of corestructures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5(splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide,among others). SIRT1 inhibition has been proposed in the treatment ofcancer, immunodeficiency virus infections, Fragile X mental retardationsyndrome and for preventing or treating parasitic diseases, whereasSIRT2 inhibitors might be useful for the treatment of cancer andneurodegenerative diseases. (Villalba et al 2012, 38(5):349-59; Chen L,Curr Med Chem. 2011; 18(13):1936-46).

Thus, there remains a need in the art for inhibitors of HDACs havinghigh selectivity within and between various HDAC classes, which canserve as therapeutic agents against a variety of diseases and disorders.There also remains a need in the art for novel inhibitors of SIRTshaving high selectivity within and between various SIRT classes, whichcan serve as therapeutic agents against a variety of diseases anddisorders. The present invention fulfills this need.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a compound of Formula I or asalt or solvate thereof:

wherein in Formula-I:

Ring A is an aromatic ring having 0-2 ring nitrogen atoms;

Ring B is a 3-7 membered saturated or unsaturated carbocyclic ring, or a3-7 membered saturated or unsaturated heterocyclic ring having 1-3 ringatoms of O, S, SO, SO₂, or NR^(a), and wherein Ring B may optionally besubstituted by one or more R^(b)s;

L₁ is a bond or a C₁-C₃ alkyl group optionally substituted by R^(b);

L₂ is a bond, a C₁-C₃ alkyl group optionally substituted by R^(b), analkenyl, or an alkynyl;

X is CH₂, O, or NR^(c);

each R^(a) and R^(b) is independently selected from the group consistingof H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I,CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e),CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e),C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), and wherein eachR^(d), R^(e) and R^(f) is independently selected from the groupconsisting of H, and optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, and wherein any of R^(d), R^(e) or R^(f) may beoptionally j oined to form additional rings; and any R^(a) and R^(b) maybe optionally joined to form additional rings;

R^(c) is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from F, Cl, Br, I, CN, NO₂, OR^(d),OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f),CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d),NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), and whereinR^(d), R^(e) and R^(f) are each independently selected from the groupconsisting of H, and optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, and wherein any of R^(d), R^(e) or R^(f) may beoptionally joined to form additional rings;

Fn is selected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V:

R⁸, R^(8′), R⁹, and R¹⁰ are each independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein theC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl may optionally be substituted,and R¹⁰ can represent single, multiple, or no substitution;

m is an integer from 0-3; and

n is an integer from 0-3.

In one embodiment, the compound is selected from the group consisting of

In another aspect, the present invention includes a compound of FormulaI-A or Formula I-B, or a salt or solvate thereof:

wherein in Formula I-A and Formula I-B:

Ring A is an aromatic ring having 0-3 ring nitrogen atoms, and whereinRing A may optionally be substituted by one or several R^(b);

Ring B is a saturated or unsaturated 3-7 membered carbocyclic ring or asaturated or unsaturated 3-7 membered heterocyclic ring having 1-3 ringatoms of O, S, SO, SO₂, or NR^(b), and wherein Ring B may optionally besubstituted by one or several R^(c);

R^(a), R^(b) and R^(c) are each independently selected from the groupconsisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e),NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f),NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d),S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and R^(a), R^(b) and R^(c) can optionally be joined to formadditional rings;

chain

is an uninterrupted chain, wherein any bond can be a single, double ortriple bond, consistent with the hybridization state of the connectedatoms, and wherein a null selection for any of the X¹ to X⁷ nodesresults in a null selection for the adjacent R groups;

X¹, X², X³, X⁴, X⁵, X⁶, and X⁷ are each independently selected from thegroup consisting of null, C, CH, CH₂, C(═O), O, N, NH, S, S(═O) andS(═O)₂;

R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′),R⁷ and R^(7′) are each independently selected from the group consistingof null, H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶, R^(6′), R⁷ and R^(7′) can optionally be connected to eachother to form various carbocyclic or heterocyclic systems; and

Fn is selected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V:

R⁸, R^(8′), R⁹, and R¹⁰ are each independently selected from the groupconsisting of null, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ canrepresent single, multiple, or no substitution; and

n is an integer of 0-3.

In one embodiment, the compound of Formula I-A has a structure selectedfrom the group consisting of Formulae VI-A, VII-A, VIII-A, IX-A, andX-A, or a salt or solvate thereof, and the compound of Formula I-B has astructure selected from the group consisting of Formulae VI-B, VII-B,VIII-B, IX-B, and X-B, or a salt or solvate thereof:

wherein in Formulae VI-A to X-B:

R¹¹, R¹², R¹³, R¹⁴, and R^(14′) are each independently selected from thegroup consisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e),NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f),NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d),S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein each R^(d), R^(e) and R^(f) isindependently selected from the group consisting of H and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹¹, R¹², R¹³, R¹⁴, and R^(14′) can optionally beconnected to each other to form various carbocyclic or heterocyclicrings;

m is an integer from 0 to 3;

q is an integer from 0 to 7;

p is an integer from 0 to 2;

J is selected from the group consisting of CH and N; and

Fn is selected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V:

R⁸, R^(8′), R⁹, and R¹⁰ are each independently selected from the groupconsisting of null, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ canrepresent single, multiple, or no substitution.

In one embodiment, the compound of Formulae VI-A, VII-A, VIII-A, IX-A,and X-A, VI-B, VII-B, VIII-B, IX-B, or X-B is selected from the groupconsisting of:

The present invention also includes a composition comprising a compoundof the invention, or a salt or solvate thereof, and at least onepharmaceutically acceptable carrier.

In one aspect, the invention relates to a composition comprising acompound of Formula I-A, and/or Formula I-B, or a salt or solvatethereof, and at least one pharmaceutically acceptable carrier.

In another aspect, the invention relates to a method of treating adisease or disorder associated with HDACs in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of Formula I-A, and/or a compound of Formula I-B,or a salt or solvate thereof. In one embodiment, the compound of FormulaI-A has a chemical structure selected from the group consisting ofFormulae VI-A, VII-A, VIII-A, IX-A, and X-A, or a salt or solvatethereof. In another embodiment, the compound of Formula I-B has achemical structure selected from the group consisting of Formulae VI-B,VII-B, VIII-B, IX-B, and X-B, or a salt or solvate thereof.

In one embodiment, the compound selectively inhibits HDAC1. In anotherembodiment, the compound selectively inhibits HDAC2. In one embodiment,the compound selectively inhibits both HDAC1 and HDAC2. In oneembodiment, the compound selectively inhibits HDAC3. In one embodiment,the compound selectively inhibits HDAC4. In one embodiment, the compoundselectively inhibits HDAC5. In one embodiment, the compound selectivelyinhibits HDAC6. In one embodiment, the compound selectively inhibitsHDAC7. In one embodiment, the compound selectively inhibits HDAC8. Inone embodiment, the compound selectively inhibits HDAC9. In oneembodiment, the compound selectively inhibits HDAC10. In one embodiment,the compound selectively inhibits HDAC11. In one embodiment, thecompound selectively inhibits SIRT1. In one embodiment, the compoundselectively inhibits SIRT2. In one embodiment, the compound selectivelyinhibits SIRT3. In one embodiment, the compound selectively inhibitsSIRT4. In one embodiment, the compound selectively inhibits SIRT5. Inone embodiment, the compound selectively inhibits SIRT6. In oneembodiment, the compound selectively inhibits SIRT7.

The present invention also includes a method of treating a disease ordisorder associated with HDACs in a subject. In one embodiment, themethod includes administering to the subject a therapeutically effectiveamount of a compound of the invention, or a salt or solvate thereof. Inone embodiment, the subject is a human. In one embodiment, the diseaseor disorder is cancer. In one embodiment, the disease or disorder is apsychiatric disease or disorder. In one embodiment, the disease ordisorder is a neurologic disease or disorder. In one embodiment, thedisease or disorder is a neurodegenerative disease or disorder. In oneembodiment, the disease or disorder is a neuroinflammation disease ordisorder. In one embodiment, the compound is administered to the subjectorally, parenterally, intravascularly, intranasally, orintrabronchially.

The present invention also includes a method of inhibiting HDACs in asubject. In one embodiment, the method includes administering to thesubject a therapeutically effective amount of a compound of theinvention, or a salt or solvate thereof. In one embodiment, the subjecthas a disease or disorder selected from the group consisting of cancer,a psychiatric disease or disorder, a neurologic disease or disorder, aneurodegenerative disease or disorder, and a neuroinflammation diseaseor disorder.

In one embodiment, the method further comprises administering to thesubject a therapeutically effective amount of an additional therapeuticagent for the treatment of a disease or disorder. In one embodiment, theadditional therapeutic agent is selected from the group consisting of animmunomodulatory drug, an immunotherapeutic drug, a DNA-damagingchemotherapeutic, a proteasome inhibitor, an anti-androgen receptor, anantiretroviral drug, a reverse-transcriptase inhibitor, achemotherapeutic drug, and an immunosuppressant.

In one aspect, the invention relates to a method of immunomodulation fororgan transplant, the method comprising administering to a patient atherapeutically effective amount of a compound of the invention or asalt or solvate thereof.

In one aspect, the invention relates to a kit for inhibiting an HDAC,comprising an amount of a compound of Formula I or a salt or solvatethereof, and an instruction manual for the use thereof.

In one aspect, the invention relates to a kit for treating a disease ordisorder associated with an HDAC in a subject, comprising an amount of acompound of the invention, or a salt or solvate thereof, and aninstruction manual for the use thereof. In one aspect, the inventionrelates to a probe for imaging, diagnosing, or theragnosting a diseaseor disorder associated with an HDAC in a subject, comprising a compoundof the invention, or a salt or solvate thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in thedrawings certain embodiments of the invention. However, the invention isnot limited to the precise arrangements and instrumentalities of theembodiments depicted in the drawings.

FIG. 1 depicts a Western blot of Compound Example 1 and Compound Example4.

FIG. 2 depicts a Western blot of Compound Example 8, Compound Example10, Compound Example 11, and Compound Example 13.

FIG. 3 depicts in vivo efficacy studies of Compound Example 4 in a Y-5Faxenograft mouse model.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds that are useful formodulating the activity of HDACs, and may be useful as therapeutics forvarious diseases and disorders, including but not limited to cancer,psychiatric disorders, neurologic disorders and neurodegenerativedisorders, inflammation, virus infection, and bone and muscle-relateddisorders such as cancer-induced cachexia.

Definitions

As used herein, each of the following terms has the meaning associatedwith it in this section. Unless defined otherwise, all technical andscientific terms used herein generally have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. Generally, the nomenclature used herein and the laboratoryprocedures in biochemistry, analytical chemistry and organic chemistryare those well-known and commonly employed in the art. Standardtechniques or modifications thereof are used for chemical syntheses andchemical analyses.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “about” as used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, is meant toencompass variations of ±20% or ±10%, more preferably ±5%, even morepreferably ±1%, and still more preferably ±0.1%

The terms “patient,” “subject,” “individual,” and the like are usedinterchangeably herein, and refer to any animal, including mammals. Incertain non-limiting embodiments, the patient, subject or individual isa human.

A “disease” is a state of health of an a subject wherein the subjectcannot maintain homeostasis, and wherein if the disease is notameliorated, the subject's health continues to deteriorate. In contrast,a “disorder” in a subject is a state of health in which the subject isable to maintain homeostasis, but in which the subject's state of healthis less favorable than it would be in the absence of the disorder. Leftuntreated, a disorder does not necessarily cause a further decrease inthe subject's state of health. As used herein, “treating a disease ordisorder” means reducing the frequency and/or severity with which asymptom of the disease or disorder is experienced by an individual.

The term “treat,” as used herein, means reducing the frequency and/orseverity of a sign or symptom of a disease or disorder experienced by asubject. Thus, “treat” and “treating” are not limited to the case wherethe subject (e.g., patient) is cured and the disease or disorder iseradicated. Rather, the present invention also contemplates treatmentthat merely reduces signs or symptoms, improves (to some degree) and/ordelays disease or disorder progression. The term “treatment” also refersto the alleviation, amelioration, and/or stabilization of signs orsymptoms, as well as a delay in the progression of signs or symptoms ofa disease or disorder. As used herein, to “alleviate” a disease ordisorder means to reduce the frequency and/or severity of one or moresigns and/or symptoms of the disease or disorder.

The term “effective amount” in a subject, as used herein, refers to anamount that provides a therapeutic or prophylactic benefit in thesubject. The term “therapeutically effective amount” refers to theamount of the compound that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought bythe researcher, veterinarian, medical doctor or other clinician. Theterm “therapeutically effective amount” includes that amount of acompound that, when administered, is sufficient to prevent developmentof, or alleviate to some extent, one or more of the signs and/orsymptoms of the disease or disorder being treated. The therapeuticallyeffective amount will vary depending on the compound, the disease ordisorder, the severity of the disease or disorder, and the age, weight,etc., of the subject to be treated.

The term “pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability. “Pharmaceutically acceptable carrier” refers to amedium that does not interfere with the effectiveness of the biologicalactivity of the active ingredient(s) and is not toxic to the host towhich it is administered.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound or molecule usefulwithin the invention within or to the patient such that it may performits intended function. Typically, such constructs are carried ortransported from one organ, or portion of the body, to another organ, orportion of the body. Each carrier must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation,including the compound useful within the invention, and not injurious tothe patient. Some examples of materials that may serve aspharmaceutically acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; surface activeagents; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations. As usedherein, “pharmaceutically acceptable carrier” also includes any and allcoatings, antibacterial and antifungal agents, and absorption delayingagents, and the like that are compatible with the activity of thecompound useful within the invention, and are physiologically acceptableto the patient. Supplementary active compounds may also be incorporatedinto the compositions. The “pharmaceutically acceptable carrier” mayfurther include a pharmaceutically acceptable salt of the compound ormolecule useful within the invention. Other additional ingredients thatmay be included in the pharmaceutical compositions used in the practiceof the invention are known in the art and described, for example inRemington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co.,1985, Easton, Pa.), which is incorporated herein by reference.

As used herein, the language “pharmaceutically acceptable salt” refersto a salt of the administered compounds prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic acids, organic acids,solvates, hydrates, or clathrates thereof.

As used herein, the term “composition” refers to a mixture of at leastone compound or molecule useful within the invention with one or moredifferent compound, molecule, or material. As used herein“pharmaceutical composition” or “pharmaceutically acceptablecomposition” refers to specific examples of compositions, wherein atleast one compound or molecule useful within the invention is mixed withone or more pharmaceutically acceptable carriers. In some instances, thepharmaceutical composition facilitates administration of the compound ormolecule to a patient. Multiple techniques of administering a compoundor molecule exist in the art including, but not limited to, intravenous,oral, aerosol, parenteral, ophthalmic, pulmonary and topicaladministration.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁-C₆means one to six carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. Most preferred is (C₁-C₆)alkyl, particularly ethyl,methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.

As used herein, the term “heteroalkyl” by itself or in combination withanother term means, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃. As used herein, the term “alkoxy”employed alone or in combination with other terms means, unlessotherwise stated, an alkyl group having the designated number of carbonatoms, as defined above, connected to the rest of the molecule via anoxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy(isopropoxy) and the higher homologs and isomers. Preferred are (C₁-C₃)alkoxy, particularly ethoxy and methoxy.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “cycloalkyl” refers to a mono cyclic orpolycyclic non-aromatic radical, wherein each of the atoms forming thering (i.e., skeletal atoms) is a carbon atom. In one embodiment, thecycloalkyl group is saturated or partially unsaturated. In anotherembodiment, the cycloalkyl group is fused with an aromatic ring.Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

Monocyclic cycloalkyls include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Dicyclic cycloalkyls include, but are not limited to,tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycycliccycloalkyls include adamantine and norbornane. The term cycloalkylincludes “unsaturated nonaromatic carbocyclyl” or “nonaromaticunsaturated carbocyclyl” groups, both of which refer to a nonaromaticcarbocycle as defined herein, which contains at least one carbon carbondouble bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers toa heteroalicyclic group containing one to four ring heteroatoms eachselected from O, S and N. In one embodiment, each heterocycloalkyl grouphas from 4 to 10 atoms in its ring system, with the proviso that thering of said group does not contain two adjacent O or S atoms. Inanother embodiment, the heterocycloalkyl group is fused with an aromaticring. In one embodiment, the nitrogen and sulfur heteroatoms may beoptionally oxidized, and the nitrogen atom may be optionallyquaternized. The heterocyclic system may be attached, unless otherwisestated, at any heteroatom or carbon atom that affords a stablestructure. A heterocycle may be aromatic or non-aromatic in nature. Inone embodiment, the heterocycle is a heteroaryl.

An example of a 3-membered heterocycloalkyl group includes, and is notlimited to, aziridine. Examples of 4-membered heterocycloalkyl groupsinclude, and are not limited to, azetidine and a beta lactam. Examplesof 5-membered heterocycloalkyl groups include, and are not limited to,pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-memberedheterocycloalkyl groups include, and are not limited to, piperidine,morpholine and piperazine. Other non-limiting examples ofheterocycloalkyl groups are:

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings),wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples of arylgroups include phenyl, anthracyl, and naphthyl. Preferred examples arephenyl and naphthyl, most preferred is phenyl.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includethe following moieties:

Examples of heteroaryl groups also include pyridyl, pyrazinyl,pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl,furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl,oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles and heteroaryls include indolyl(particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl),1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2-and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl,1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl,benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl),2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl(particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl,thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, andquinolizidinyl.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup. The term “substituted” further refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or pentasubstitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.In one embodiment, the substituents vary in number between one and four.In another embodiment, the substituents vary in number between one andthree. In yet another embodiment, the substituents vary in numberbetween one and two.

As used herein, the term “optionally substituted” means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

In one embodiment, the substituents are independently selected from thegroup consisting of oxo, halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,alkyl (including straight chain, branched and/or unsaturated alkyl),substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, fluoro alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy,—S-alkyl, S(═O)₂alkyl, —C(═O)NH[substituted or unsubstituted alkyl, orsubstituted or unsubstituted phenyl], —C(═O)N[H or alkyl]₂,—OC(═O)N[substituted or unsubstituted alkyl]₂, —NHC(═O)NH[substituted orunsubstituted alkyl, or substituted or unsubstituted phenyl],—NHC(═O)alkyl, —N[substituted or unsubstituted alkyl]C(═O)[substitutedor unsubstituted alkyl], —NHC(═O)[substituted or unsubstituted alkyl],—C(OH)[substituted or unsubstituted alkyl]₂, and —C(NH₂)[substituted orunsubstituted alkyl]₂. In another embodiment, by way of example, anoptional substituent is selected from oxo, fluorine, chlorine, bromine,iodine, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CF₃, —CH₂CF₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OCF₃, —OCH₂CF₃,—S(═O)₂—CH₃, —C(═O)NH₂, —C(═O)—NHCH₃, —NHC(═O)NHCH₃, —C(═O)CH₃, and—C(═O)OH. In yet one embodiment, the substituents are independentlyselected from the group consisting of C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy,halo, amino, acetamido, oxo and nitro. In yet another embodiment, thesubstituents are independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ alkoxy, halo, acetamido, and nitro. As used herein,where a substituent is an alkyl or alkoxy group, the carbon chain may bebranched, straight or cyclic, with straight being preferred.

As used herein, an “instructional material” or “instruction manual”includes a publication, a recording, a diagram, or any other medium ofexpression which can be used to communicate the usefulness of thecomposition of the invention for its designated use. The instructionalmaterial of the kit of the invention may, for example, be affixed to acontainer which contains the composition or be shipped together with acontainer which contains the composition. Alternatively, theinstructional material may be shipped separately from the container withthe intention that the instructional material and the composition beused cooperatively by the recipient.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range and, when appropriate,partial integers of the numerical values within ranges. For example,description of a range such as from 1 to 6 should be considered to havespecifically disclosed subranges such as from 1 to 3, from 1 to 4, from1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well asindividual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5,5.3, and 6. This applies regardless of the breadth of the range.

Compounds of the Invention

In one aspect, the invention relates to a compound with the chemicalstructure depicted in Formula I, or a pharmaceutically acceptable salt,or solvate thereof:

wherein in Formula I:

Ring A is an aromatic ring having 0-2 ring nitrogen atoms;

Ring B is a 3-7 membered saturated or unsaturated carbocyclic ring, or a3-7 membered saturated or unsaturated heterocyclic ring having 1-3 ringatoms of O, S, SO, SO₂, or NR^(a), and wherein Ring B may optionally besubstituted by one or more R^(b)s;

L₁ is a bond or a C₁-C₃ alkyl group optionally substituted by R^(b);

L₂ is a bond, a C₁-C₃ alkyl group optionally substituted by R^(b), analkenyl, or an alkynyl;

X is CH₂, O, or NR^(C);

each R^(a) and R^(b) is independently selected from the group consistingof H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I,CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e),CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e),C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), and wherein eachR^(d), R^(e) and R^(f) is independently selected from the groupconsisting of H, and optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, and wherein any of R^(d), R^(e) or R^(f) may beoptionally j oined to form additional rings; and any R^(a) and R^(b) maybe optionally joined to form additional rings;

R^(c) is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from F, Cl, Br, I, CN, NO₂, OR^(d),OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f),CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d),NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), and whereinR^(d), R^(e) and R^(f) are each independently selected from the groupconsisting of H, and optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, and wherein any of R^(d), R^(e) or R^(f) may beoptionally joined to form additional rings;

Fn is selected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V:

R⁸, R^(8′), R⁹, and R¹⁰ are each independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein theC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl may optionally be substituted,and R¹⁰ can represent single, multiple, or no substitution;

m is an integer from 0-3; and

n is an integer from 0-3.

In one embodiment, Ring A is a 6-membered aromatic ring having 0-2 ringnitrogen atoms. In one embodiment, Ring A is phenyl or pyridyl.

In one embodiment, L₂ is selected from the group consisting of a bond, aCi alkyl group, an alkenyl, and an alkynyl.

In one embodiment, Fn is a group of Formula III.

In one embodiment, R⁸ is H.

In one embodiment, R⁹ is H.

In one embodiment, R¹⁰ is selected from the group consisting of H, aryl,substituted aryl, and heteroaryl. In one embodiment, R¹⁰ is selectedfrom the group consisting of H, substituted phenyl, and thiophenyl.

In one embodiment, R¹⁰ is selected from the group consisting of and

In one embodiment, Fn is a group of Formula II.

In one embodiment, R⁸ is H.

In one embodiment, R⁹ is H.

In one embodiment, Fn is selected from the group consisting of

In one embodiment, L₁ is selected from the group consisting of a bond, aC₁ alkyl group, and a C₁ alkyl group substituted with R^(b). In oneembodiment, L₁ is selected from the group consisting of a bond, a C₁alkyl group, and a C₁ alkyl group substituted with a —CH₃ group.

In one embodiment, X is selected from the group consisting of CH₂ and O.

In one embodiment, Ring B is selected from the group consisting of

Non-limiting examples of Ring B include

Non-limiting examples of compounds of the invention include

In one embodiment, the compound is

In one aspect, the present invention includes a compound of Formula I-Aor Formula I-B, or a salt or solvate thereof:

wherein in Formula I-A and Formula I-B:

Ring A is an aromatic ring having 0-3 ring nitrogen atoms, and whereinRing A may optionally be substituted by one or more R^(b)s;

Ring B is a saturated or unsaturated 3-7 membered carbocyclic ring or asaturated or unsaturated 3-7 membered heterocyclic ring having 1-3 ringatoms of O, S, SO, SO₂, or NR^(b), and wherein Ring B may optionally besubstituted by one or more R^(c)s;

R^(a), R^(b) and R^(c) are each independently selected from the groupconsisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e),NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f),NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d),S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and R^(a), R^(b) and R^(c) can optionally be joined to formadditional rings;

chain

is an uninterrupted chain, wherein any bond can be a single, double ortriple bond, consistent with the hybridization state of the connectedatoms, e.g. if X² is an sp hybridized carbon atom and X³ is also an sphybridized carbon atom, then the X²-X³ bond is a triple C—C bond, etc.,wherein a null selection for any of the X¹ to X⁷ nodes will result inconnecting the adjacent nodes, e.g. if X⁵ is null, then X⁴ connects toX⁶, or if X⁴ and X⁵ are both null, then X³ connects with X⁶, etc., andwherein a null selection for any of the X¹ to X⁷ nodes will result in anautomatic null selection for the adjacent R groups, e.g. if X³ is null,then R³ and R^(3′) are both automatically null, etc.;

X¹, X², X³, X⁴, X⁵, X⁶, and X⁷ are each independently selected from thegroup consisting of null, C, CH, CH₂, C(═O), O, N, NH, S, S(═O) andS(═O)₂;

R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′),R⁷ and R^(7′) are each independently selected from the group consistingof null, H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶, R^(6′), R⁷ and R^(7′) can optionally be connected to eachother to form various carbocyclic or heterocyclic systems; and

Fn is selected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V:

R⁸, R^(8′), R⁹, and R¹⁰ are each independently selected from the groupconsisting of null, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ canrepresent single, multiple, or no substitution; and

n is an integer of 0-3.

In one embodiment, Ring A is phenyl.

In one embodiment, Ring B is a saturated 3-7 membered heterocyclic ringhaving 1-3 ring atoms of O, S, SO, SO₂, or NR^(b). In one embodiment,Ring B is selected from the group consisting of: dioxalane,tetrahydrofuran, piperidine, pyrrolidine, and azetidine; wherein Ring Bmay optionally be substituted by one or several R^(c).

In one embodiment, Ring B is a saturated 3-7 membered carbocyclic ring.In one embodiment, Ring B is selected from the group consisting ofcyclopropane and cyclobutane.

In one embodiment, Ring B is selected from the group consisting of

Non-limiting examples of Ring B include

In one embodiment, R^(c) is selected from the group consisting ofhydrogen, alkyl, C(═O)NR^(d)R^(e), C(═O)R^(d), and cycloalkyl. In oneembodiment, R^(c) is hydrogen. In one embodiment, R^(c) is alkyl. In oneembodiment, the alkyl is a methyl group. In one embodiment, R^(c) isC(═O)NR^(d)R^(e) wherein one of R^(d) or R^(e) is hydrogen and the otherof R^(d) or R^(e) is a methyl group. In one embodiment, R^(c) isC(═O)NR^(d)R^(e) wherein one of R^(d) or R^(e) is hydrogen and the otherof R^(d) or R^(e) is an isopropyl group. In one embodiment, R^(c) isC(═O)R^(d) wherein R^(d) is a methyl group. In one embodiment, R^(c) isC(═O)NR^(d)R^(e) wherein R^(d) and R^(e) are each a methyl group. In oneembodiment, R^(c) is C(═O)R^(d) wherein R^(d) is an isopropyl group. Inone embodiment, R^(c) is C(═O)R^(d) wherein R^(d) is a cyclopropane. Inone embodiment, R^(c) is a cycloalkyl group. In one embodiment, thecycloalkyl group is a cyclopropane.

In one embodiment, R^(d) is selected from the group consisting ofhydrogen, alkyl, and cycloalkyl.

In one embodiment, R^(e) is selected from the group consisting ofhydrogen and alkyl.

In one embodiment, at least one of X¹, X², X³, X⁴, X⁵, X⁶, and X⁷ is notnull.

In one embodiment, chain

is selected from the group consisting of

wherein

R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ are each independently selected from thegroup consisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e),NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f),NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d),S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein each R^(d), R^(e) and R^(f) isindependently selected from the group consisting of H and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ can optionally beconnected to each other to form various carbocyclic or heterocyclicrings;

m is an integer from 0 to 3;

q is an integer from 0 to 7;

p is an integer from 0 to 2; and

J is selected from the group consisting of CH and N.

In one embodiment, the compound is a compound of Formula I-A. In anotherembodiment, the compound is a compound of Formula I-B.

In one embodiment, the compound is selected from the group consisting ofFormulae VI-A, VII-A, VIII-A, IX-A, X-A, VI-B, VII-B, VIII-B, IX-B, andX-B, or a salt or solvate thereof:

wherein in Formulae VI-A to X-B:

R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ are each independently selected from thegroup consisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e),NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f),NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d),S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein each R^(d), R^(e) and R^(f) isindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ can optionally be joinedto each other to form various carbocyclic or heterocyclic rings e.g. ifR¹² is CH₂ and R¹³ is OCH₂, they can join to form a bridgedtetrahydrofuran ring, etc.;

m is an integer from 0 to 3;

q is an integer from 0 to 7;

p is an integer from 0 to 2;

J is selected from the group consisting of CH and N; and

Fn is selected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V:

R⁸, R^(8′), R⁹, and R¹⁰ are each independently selected from the groupconsisting of null, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ canrepresent single, multiple, or no substitution.

In one embodiment, the compound has a chemical structure that containsisotope atoms D, ¹³C, and ¹⁹F.

In one embodiment, the compound of Formulae VI-A, VII-A, VIII-A, IX-A,and X-A, VI-B, VII-B, VIII-B, IX-B, or X-B is selected from the groupconsisting of:

Formulations, Prodrugs, and Salts

In one embodiment, the invention provides use of the compounds of theinvention for the manufacture and preparation of medicaments for use intherapy. In one embodiment, the present invention provides compounds ofuseful for the manufacture and preparation of medicaments for use intreating and preventing diseases and disorders. In one embodiment, thediseases or disorders are associated with HDAC. In one embodiment, aneffective inhibitor of HDACs retains its activity when mixed with anacceptable pharmaceutical carrier. In one embodiment, the inventionfurther provides novel compounds and novel pharmaceutical compositionscomprising the same and at least one pharmaceutically acceptablecarrier.

The invention includes prodrugs of the compounds of the invention.“Prodrug,” as used herein, means a compound which is convertible in vivoby metabolic means (e.g., by hydrolysis) to a compound of the presentinvention. Various forms of prodrugs are known in the art, for example,as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen et al. (ed). “Design and Application ofProdrugs,” Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard et al., 1992, J. Drug Deliv. Rev. 8:1-38, Bundgaard,1988, J. Pharm. Sci. 77:285 et seq.; and Higuchi and Stella (eds.),Prodrugs as Novel Drug Delivery Systems, American Chemical Society(1975). In one non-limiting example, the esters and amides of thealpha-carboxylic acid are prepared as prodrugs to improve oralbioavailability, whereby the ester or amide is stable in the stomach andgastrointestinal tract, is optimally transported across the lining ofthe gastrointestinal tract into the bloodstream, and is then convertedby the ubiquitous esterases or amidases in the blood to the carboxylicacid moiety. In another non-limiting example, the ester prodrug is themethyl, ethyl, n-propyl or i-propyl ester. In another non-limitingexample, the amide prodrug is the isopropyl amide or the2,2,2-trifluoroethyl amide.

The compounds useful in the invention may form salts with acids orbases, and such salts are included in the present invention. In oneembodiment, the salts are pharmaceutically-acceptable salts. The term“salts” embraces addition salts of free acids or free bases that arecompounds useful within the invention. The term “pharmaceuticallyacceptable salt” refers to salts that possess toxicity profiles within arange that affords utility in pharmaceutical applications.Pharmaceutically unacceptable salts may nonetheless possess propertiessuch as high crystallinity, which have utility in the practice of thepresent invention, such as for example utility in process of synthesis,purification or formulation of compounds useful within the invention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compoundsuseful in the invention include, for example, metallic salts includingalkali metal, alkaline earth metal and transition metal salts such as,for example, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. All of these salts may be prepared from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

Methods of the Invention

In one aspect, the present invention includes methods for inhibitingHDACs. In one embodiment, the invention includes methods for treating,in a subject, a disease or disorder associated with HDACs. In oneembodiment, the invention includes methods for inhibiting HDACs in asubject in need thereof. In one embodiment, the method includesadministering a compound of the invention to the subject. In oneembodiment, the subject is a human. In one embodiment, the subject has adisease or disorder selected from the group consisting of cancer, apsychiatric disease or disorder, a neurologic disease or disorder, aneurodegenerative disease or disorder, and a neuroinflammation diseaseor disorder.

In one embodiment, the invention includes a method of preventing ortreating a disease or disorder, comprising administering a compound ofthe invention to a subject in need of such prevention or treatment,wherein the amount of the compound is sufficient for the prevention ortreatment of the disease or disorder in the subject.

In one aspect, the present invention also includes methods for treatinga disease or disorder associated with HDACs in a subject in needthereof. In one embodiment, the subject is a human. In one embodiment,the method includes administering a compound of the invention to thesubject.

In one embodiment, the amount of the compound administered is sufficientfor the prevention or treatment of the disease or disorder in thesubject.

In one embodiment, the method comprises administering to the subject atherapeutically effective amount of a compound of the invention. In oneembodiment, the compound is a compound of Formula I, or a salt orsolvate thereof. In one embodiment, the compound is a compound ofFormula I-A or Formula I-B, or a salt or solvate thereof. In oneembodiment, the compound is a compound of Formula I-A, or a salt orsolvate thereof. In one embodiment, the compound is a compound ofFormula I-B, or a salt or solvate thereof. In one embodiment, thecompound of Formula I-A has a structure selected from the groupconsisting of Formulae VI-A, VII-A, VIII-A, IX-A, and X-A, or a salt orsolvate thereof. In one embodiment, the compound of Formula I-B has astructure selected from the group consisting of Formulae VI-B, VII-B,VIII-B, IX-B, and X-B, or a salt or solvate thereof.

In one aspect, the invention relates to a composition comprising acompound of the invention, or a salt or solvate thereof, and at leastone pharmaceutically acceptable carrier.

In one aspect, the invention relates to a method of inhibiting HDAC. Inone embodiment, the compound of the invention inhibits two or moreHDACs. In another embodiment, the compound of the invention inhibits atleast one HDAC. In another embodiment, the compound of the inventioninhibits only a small group of HDACs. In another embodiment, thecompound of the invention inhibits only one class of HDACs. In oneembodiment, the compound of the invention selectively inhibits class IHDACs. In another embodiment, the compound of the invention selectivelyinhibits class IIA HDACs. In another embodiment, the compound of theinvention selectively inhibits class IIB HDACs. In another embodiment,the compound of the invention selectively inhibits class III HDACs. Inyet another embodiment, the compound of the invention selectivelyinhibits class IV HDACs.

In one embodiment, the compound of the invention selectively inhibitsonly part of a class of HDACs. In one embodiment, the compound of theinvention inhibits only one HDAC. In one embodiment, the compound of theinvention selectively inhibits HDAC1. In one embodiment, the compound ofthe invention selectively inhibits HDAC2. In one embodiment, thecompound of the invention selectively inhibits HDAC3. In one embodiment,the compound of the invention selectively inhibits HDAC4. In oneembodiment, the compound of the invention selectively inhibits HDAC5. Inone embodiment, the compound of the invention selectively inhibitsHDAC6. In one embodiment, the compound of the invention selectivelyinhibits HDAC7. In one embodiment, the compound of the inventionselectively inhibits HDAC8. In one embodiment, the compound of theinvention selectively inhibits HDAC9. In one embodiment, the compound ofthe invention selectively inhibits HDAC10. In one embodiment, thecompound of the invention selectively inhibits HDAC11.

In one aspect, the invention relates to a method of inhibiting SIRT. Inone embodiment, the compound of the invention inhibits two or moreSIRTs. In one embodiment, the compound of the invention inhibits atleast one SIRT. In one embodiment, the compound of the inventioninhibits only one SIRT. In one embodiment, the compound of the inventionselectively inhibits SIRT1. In one embodiment, the compound of theinvention selectively inhibits SIRT2. In one embodiment, the compound ofthe invention selectively inhibits SIRT3. In one embodiment, thecompound of the invention selectively inhibits SIRT4. In one embodiment,the compound of the invention selectively inhibits SIRT5. In oneembodiment, the compound of the invention selectively inhibits SIRT6. Inone embodiment, the compound of the invention selectively inhibitsSIRT7.

In one embodiment, the invention provides a method of treatingHDAC-associated diseases and disorders. In one embodiment, the methodincludes administering to a patient a therapeutically effective amountof a compound of the invention. In one embodiment, the inventionprovides a method of treating a disease or disorder related to theenzymatic control of the acetylation state of protein lysine residues,more specifically those contained in the N-terminal extensions of thecore histones. In one embodiment, invention provides a method oftreating a disease or disorder associated with the overexpression of oneor more HDACs. In one embodiment, the disease or disorder is cancer,such as, but not limited to, multiple myeloma, leukemia, lymphoma,breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer,bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skinor eye melanoma, sarcoma of the uterus, ovarian cancer, rectal cancer,anal cancer, colorectal cancer, fallopian tube carcinoma, endometriumcarcinoma, cervical cancer, small intestine cancer, endocrine glandcancer, thyroid cancer, parathyroid gland cancer, renal cell carcinoma,soft tissue sarcoma, urethra cancer, prostate cancer, bronchial cancer,myeloma, neuroma, cutaneous squamous cell carcinoma, or the like.

In one aspect, the invention provides a method of treating a disease ordisorder selected from the group consisting of cancer, a psychiatricdisease or disorder, a neurologic disease or disorder, aneurodegenerative disease or disorder, and a neuroinflammation diseaseor disorder. In one embodiment, the method includes administering to apatient a therapeutically effective amount of a compound of theinvention.

In one aspect, the invention provides a method of treating aneurological disease or disorder. In one embodiment, the inventionprovides a method of treating an inflammatory disease or disorder. Inother various embodiments, the diseases and disorders include, but arenot limited to, diseases and disorders related to cell migration, cellspreading, immune synapse formation, viral infection, the degradation ofmisfolded proteins and stress granule (SG) formation. In one embodiment,the disease or disorder is Alzheimer's disease. In one embodiment, thedisease or disorder is an autoimmune disease or disorder. In othervarious embodiments, the diseases and disorders treatable by thecompound of the invention include, but are not limited to, diseases anddisorders related to neurological disease, a neurodegenerative disorder,a neurodegenerative disease, neuroinflammation, pain, epilepsy, stroke,traumatic brain injury, allograft rejection, or a parasite relateddisease. In one embodiment, the neuroinflammation disease or disorder isthe Charcot-Marie-Tooth (CMT) disease. In other embodiments, a diseaseor disorder is Huntington's disease, Parkinson's disease, ischemicstroke, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy,pain, anxiety and depression, bone and muscle-related disorders such ascancer-induced cachexia, Gaucher's disease, and neuroblastoma.

In one embodiment, the disease or disorder is a pathological autoimmunedisorder such as juvenile oligoarthritis, collagen-induced arthritis,adjuvant-induced arthritis, Sjogren's syndrome, multiple sclerosis,experimental autoimmune encephalomyelitis, inflammatory bowel disease(for example, Crohn's disease, ulcerative colitis), autoimmune gastricatrophy, pemphigus vulgaris, psoriasis, vitiligo, type 1 diabetes,non-obese diabetes, myasthenia gravis, Grave's disease, Hashimoto'sthyroiditis, sclerosing cholangitis, sclerosing sialadenitis, systemiclupus erythematosis, autoimmune thrombocytopenia purpura, Goodpasture'ssyndrome, Addison's disease, systemic sclerosis, polymyositis,dermatomyositis, autoimmune hemolytic anemia, pernicious anemia, and thelike.

In another aspect, the invention provides a method of immunomodulationfor organ transplant. In one embodiment, the method includesadministering to a patient a therapeutically effective amount of acompound of the invention. In one embodiment, the method confersimproved or superior retention of organ transplants.

In one embodiment of the method of the invention, the compound of theinvention is administered in combination with a second therapeutic agentfor the treatment of a disease or disorder. In one embodiment, thesecond therapeutic agent is administered simultaneously, prior to, orafter administration of the compound of the invention. In yet anotherembodiment, the second therapeutic agent is co-administered with thecompound of the invention. In one embodiment, the second therapeuticagent is co-administered and co-formulated with the compound of theinvention. In one embodiment, the second therapeutic agent is aDNA-damaging chemotherapeutics such as idarubicin and cytarabine for thetreatment of AML and MDS. In one embodiment, the second therapeuticagent is a proteasome inhibitor such as bortezomib for the treatment ofrelapsing and/or refractory multiple myeloma and lymphoma. In anotherembodiment, the second therapeutic agent is an anti-androgen receptoragent such as bicalutamide for the treatment of prostate cancer.

In some embodiments, one or more additional pharmaceutical agents can beused, such as, for example, immunomodulatory or immunotherapeutic drugs,such as immune checkpoint inhibitor monoclonal antibodies, thalidomide,lenalidomide (Len) and pomalidomide, steroids, such as dexamethasone,anticancer antibodies, such as nivolumab and ipilimumab, proteasomeinhibitors, such as bortezomib, salinosporamide, anticancer drugs, suchas romidepsin, and taxanes, oncolytic viral therapy agents, such asadenovirus, reovirus, or herpes simplex.

In one embodiment, the second therapeutic agent is a DNA-damagingchemotherapeutics such as idarubicin and cytarabine for the treatment ofAML and MDS. In one embodiment, the second therapeutic agent is aproteasome inhibitor such as bortezomib for the treatment of relapsingand/or refractory multiple myeloma and lymphoma. In one embodiment, thesecond therapeutic agent is an antiandrogen receptor agent such asbicalutamide for the treatment of prostate cancer.

In some embodiments, the second therapeutic agent is an antiretroviraldrug. In other embodiments, the second therapeutic agent is areverse-transcriptase inhibitor. In other embodiments, the secondtherapeutic agent can be lamivudine, zidovudine, lopinavir, ritonavir,abacavir, tenofovir, emtricitabine, rilpivirine, efavirenz,elvitegravir, cobicistat, dolutegravir, darunavir, atazanavir, andraltegravir.

In some embodiments, the compound of the invention may be administeredto a subject in conjunction with (e.g., before, simultaneously, orfollowing) any number of relevant treatment modalities includingchemotherapy, such as kinase inhibitors Afatinib, Neratiniab, Lapatinibetc., radiation, immunosuppressive agents, immunomodulators, such ascyclosporin, azathioprine, methotrexate, mycophenolate, Pomalidomide,Lenalidomide and FK506, antibodies, or other immunoablative agents suchas CAM PATH, anti-CD3 antibodies, agents targeting programmed deathreceptor-1 (PD-1) and ligand (PD-L1) or other antibody therapies,cytoxin, fludaribine, cyclosporin, FK506, rapamycin, mycophenolic acid,steroids, FR901228, cytokines, and irradiation. These drugs inhibiteither the calcium dependent phosphatase calcineurin (cyclosporine andFK506) or inhibit the p70S6 kinase that is important for growth factorinduced signaling (rapamycin) (Liu et al., Cell 66:807-815, 1991;Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin.Immun. 5:763-773, 1993; Booth et al, 2017 Oncotarget, 8:90262-90277). Ina further embodiment, the compounds of the present invention areadministered to a patient in conjunction with (e.g., before,simultaneously or following) bone marrow transplantation, T cellablative therapy using either chemotherapy agents such as, fludarabine,external-beam radiation therapy (XRT), cyclophosphamide, or antibodiessuch as OKT3 or CAMPATH. In another embodiment, the compounds of thepresent invention are administered following B-cell ablative therapysuch as agents that react with CD20, e.g., Rituxan.

Without wishing to be bound by any particular theory, it is believedthat the ability of the compounds of the invention to regulate thebiological activity of HDACs provides methods of treating HDACs relateddisorders. For example, the compounds of the invention can be used tosuppress HDACs activity, whether HDACs are overexpressed or not.

Dosing

The compounds of the invention, alone or in combination with anothertherapeutic agent, can be administered to a cell, a tissue, or a subjectto provide a therapeutic effect. Methods for the safe and effectiveadministration of the compounds of the invention are known to thoseskilled in the art. For instance, the administration of HDACs inhibitorsis described in the literature.

Dosages of the compounds of the invention range from about 0.1 μg/day to10,000 mg/day, from about 1 μg/day to 1000 mg/day, and from about 10μg/day to 100 mg/day, and any and all whole or partial increments therebetween.

Stated in terms of subject body weight, dosages range from about 0.1μg/kg/day to about 1000 mg/kg/day, from about 10 μg/kg/day to about 500mg/kg/day, from about 20 μg/kg/day to about 100 mg/kg/day, from about 50μg/kg/day to about 50 mg/kg/day, and from about 0.10 mg/kg/day to about5 mg/kg/day, and any and all whole or partial increments there between.

Oral dosages of the compounds of the invention range from about 0.1μg/day to about 10,000 mg/day, from about 1 μg/day to about 1000 mg/day,from about 10 μg/day to about 100 mg/day, and from about 8 mg/day toabout 80 mg/day, and any and all whole or partial increments therebetween.

Stated in terms of subject body weight, oral dosages range from about0.1 μg/kg/day to about 1000 mg/kg/day, from about 10 μg/kg/day to about500 mg/kg/day, from about 20 μg/kg/day to about 100 mg/kg/day, fromabout 50 μg/kg/day to about 50 mg/kg/day, and from about 0.10 mg/kg/dayto about 5 mg/kg/day, and any and all whole or partial increments therebetween.

The compounds of the invention for administration can be administered ina dose range of from about 1 ng to about 10,000 mg, about 5 ng to about9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg,about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng toabout 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about4,500 mg, about 500 ng to about 4,000 mg, about 1 μg to about 3,500 mg,about 5 μg to about 3,000 mg, about 10 μg to about 2,600 mg, about 20 μgto about 2,575 mg, about 30 μg to about 2,550 mg, about 40 μg to about2,500 mg, about 50 μg to about 2,475 mg, about 100 μg to about 2,450 mg,about 200 μg to about 2,425 mg, about 300 μg to about 2,000, about 400μg to about 1,175 mg, about 500 μg to about 1,150 mg, about 0.5 mg toabout 1,125 mg, about 1 mg to about 1,100 mg, about 1.25 mg to about1,075 mg, about 1.5 mg to about 1,050 mg, about 2.0 mg to about 1,025mg, about 2.5 mg to about 1,000 mg, about 3.0 mg to about 975 mg, about3.5 mg to about 950 mg, about 4.0 mg to about 925 mg, about 4.5 mg toabout 900 mg, about 5 mg to about 875 mg, about 10 mg to about 850 mg,about 20 mg to about 825 mg, about 30 mg to about 800 mg, about 40 mg toabout 775 mg, about 50 mg to about 750 mg, about 100 mg to about 725 mg,about 200 mg to about 700 mg, about 300 mg to about 675 mg, about 400 mgto about 650 mg, about 500 mg, or about 525 mg to about 625 mg, and anyand all whole or partial increments there between.

In some embodiments, the dose of the compound of the invention is fromabout 0.0001 mg to about 25 mg. In some embodiments, a dose of acompound of the invention used in compositions described herein is lessthan about 100 mg, or less than about 80 mg, or less than about 60 mg,or less than about 50 mg, or less than about 30 mg, or less than about20 mg, or less than about 10 mg, or less than about 5 mg, or less thanabout 2 mg, or less than about 0.5 mg. Similarly, in some embodiments, adose of a second compound as described herein is less than about 1000mg, or less than about 800 mg, or less than about 600 mg, or less thanabout 500 mg, or less than about 400 mg, or less than about 300 mg, orless than about 200 mg, or less than about 100 mg, or less than about 50mg, or less than about 40 mg, or less than about 30 mg, or less thanabout 25 mg, or less than about 20 mg, or less than about 15 mg, or lessthan about 10 mg, or less than about 5 mg, or less than about 2 mg, orless than about 1 mg, or less than about 0.5 mg, and any and all wholeor partial increments there between.

Enantiomeric or Diastereomeric Forms, and Isotope Substitutions.

It will be understood that when compounds of the invention contain oneor more chiral centers, the compounds may exist in, and may be isolatedas pure enantiomeric or diastereomeric forms or as racemic mixtures. Thepresent invention therefore includes any possible enantiomers,diastereomers, racemates or mixtures thereof of the compounds of theinvention that are efficacious in inhibiting HDACs. The isomersresulting from the presence of a chiral center comprise a pair ofnon-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Enantiomers maybe purified from racemic mixtures by well-known chiral separationtechniques. According to one such method, a racemic mixture of acompound having the structure of Formula I or a chiral intermediatethereof, is separated into 99% wt % pure optical isomers by HPLC using asuitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan), operated according to the manufacturer's instructions. By“isolated optical isomer” it is understood a compound that has beensubstantially purified from the corresponding optical isomer(s) of thesame formula. In some embodiments, the isolated isomer is at least about80% pure by weight. In some embodiments, the isolated isomer is at leastabout 90% pure by weight. In some embodiments, the isolated isomer is atleast about 98% pure by weight. In some embodiments, the isolated isomeris at least about 99% pure, by weight. Diastereoisomeric pairs may beresolved by known separation techniques including normal and reversephase chromatography, and crystallization.

Isotopic substitutions can be applied to compounds of the invention.Isotope atoms include but not limited to D and T for substitution of H;C¹³ for C¹²; or F¹⁹ for F¹⁸.

Pharmaceutical Composition

For administration of a compound of the present invention to a subject,the compound can be suspended in any pharmaceutically acceptablecarrier, for example, sterile water or buffered aqueous carriers, suchas glycerol, water, saline, ethanol and other pharmaceuticallyacceptable salt solutions such as phosphates and salts of organic acids.Examples of these and other pharmaceutically acceptable carriers aredescribed in Remington's Pharmaceutical Sciences (1991, Mack PublicationCo., New Jersey), the disclosure of which is incorporated by referenceas if set forth in its entirety herein.

The pharmaceutical compositions comprising a compound of the inventionmay be prepared, packaged, or sold in the form of a sterile injectableaqueous or oily suspension or solution. This suspension or solution maybe formulated according to the known art, and may comprise, in additionto the active ingredient, additional ingredients such as dispersingagents, wetting agents, or suspending agents described herein. Suchsterile injectable formulations may be prepared using a non-toxicparenterally-acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, butare not limited to, Ringer's solution, isotonic sodium chloridesolution, and fixed oils such as synthetic mono- or di-glycerides.

The compositions of the invention are preferably administered to thesubject as a pharmaceutical or veterinary composition, which includessystemic and topical formulations. Among these, preferred areformulations suitable for inhalation, or for respirable, buccal, oral,rectal, vaginal, nasal, intrapulmonary, ophthalmic, optical,intracavitary, intratraccheal, intraorgan, topical (including buccal,sublingual, dermal and intraocular), parenteral (including subcutaneous,intradermal, intramuscular, intravenous and intraarticular) andtransdermal administration, among others. The route(s) of administrationwill be readily apparent to the skilled artisan and will depend upon anynumber of factors including the type and severity of the disease beingtreated, the type and age of the veterinary or human patient beingtreated.

The compositions of the invention may be administered to the lungs of asubject by any suitable means, but are preferably administered bygenerating an aerosol or spray comprised of respirable, inhalable, nasalor intrapulmonarily delivered particles comprising the active compound,which particles the subject inhales, i.e., by inhalation administration.The respirable particles may be liquid or solid. Particles comprisingthe active compound for practicing the present invention should includeparticles of respirable or inhalable size; that is, particles of a sizesufficiently small to pass through the mouth and larynx upon inhalationand into the bronchi and alveoli of the lungs. In general, particlesranging from about 0.05, about 0.1, about 0.5, about 1, about 1.5 toabout 5, about 6, about 7, about 8, about 10 microns in size, moreparticularly particles about 0.5 to less than about 5 microns in size,are respirable or inhalable. When particles of nonrespirable size areincluded in the aerosol or spray, they tend to deposit in the throat andbe swallowed. Thus, the quantity of non-respirable particles in theaerosol or spray is preferably minimized when intended for respirableadministration or by inhalation. For nasal or intrapulmonaryadministration, a particle size in the range of about 10, about 11,about 15, about 20 to about 25, about 30, about 40, about 50, andsometimes even up to about 100 and about 500 microns is preferred toensure retention in the nasal or pulmonary cavity. Pulmonaryinstillation is particularly useful in treating newborns.

Liquid pharmaceutical compositions of the compound of the invention forproducing an aerosol or spray may be prepared by combining the activecompound with a stable vehicle, such as sterile pyrogen free water.Solid particulate compositions containing respirable dry particles ofmicronized active compound may be prepared by grinding dry activecompound with a mortar and pestle, and then passing the micronizedcomposition through a 400 mesh screen to break up or separate out largeagglomerates. A solid particulate composition comprised of the activecompound may optionally contain a dispersant which serves to facilitatethe formation of an aerosol. A suitable dispersant is lactose, which maybe blended with the active compound in any suitable ratio, e.g., a 1 to1 ratio by weight. Other therapeutic and formulation compounds may alsobe included, such as a surfactant to improve the state of surfactant inthe lung and to help with the absorption of the active agent.

Aerosols of liquid particles comprising an active compound may beproduced by any suitable means, such as with a nebulizer. See, e.g.,U.S. Pat. No. 4,501,729. Nebulizers are commercially available deviceswhich transform solutions or suspensions of the active ingredient into atherapeutic aerosol mist either by means of acceleration of a compressedgas, typically air or oxygen, through a narrow venturi orifice or bymeans of ultrasonic agitation. Suitable compositions for use innebulizer consist of the active ingredient in liquid carrier, the activeingredient comprising up to 40% w/w of the compositions, but preferablyless than 20% w/w, and the carrier is typically water or a diluteaqueous alcoholic solution, preferably made isotonic with body fluids bythe addition of, for example sodium chloride. Optional additives includepreservatives if the composition is not prepared sterile, for example,methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils,buffering agents and surfactants.

Aerosols of solid particles comprising the active compound may likewisebe produced with any sold particulate medicament aerosol generator.Aerosol generators for administering solid particulate medicaments to asubject produce particles which are respirable, as explained above, andthey generate a volume of aerosol containing a predetermined metereddose of a medicament at a rate suitable for human administration.Examples of such aerosol generators include metered dose inhalers andinsufflators.

Pharmaceutical compositions that are useful in the methods of theinvention may be administered systemically in oral solid formulations,ophthalmic, suppository, aerosol, topical or other similar formulations.In addition to the compounds of the invention, or a biologicalequivalent thereof, such pharmaceutical compositions may containpharmaceutically-acceptable carriers and other ingredients known toenhance and facilitate drug administration.

The pharmaceutical compositions described herein can be prepared alone,in a form suitable for administration to a subject, or thepharmaceutical composition may comprise the active ingredient and one ormore pharmaceutically acceptable carriers, one or more additionalingredients, or some combination of these. The active ingredient may bepresent in the pharmaceutical composition in the form of aphysiologically acceptable ester or salt, such as in combination with aphysiologically acceptable cation or anion, as is well known in the art.

As used herein, the term “pharmaceutically acceptable carrier” means achemical composition with which the active ingredient may be combinedand which, following the combination, can be used to administer theactive ingredient to a subject.

As used herein, the term “physiologically acceptable” ester or saltmeans an ester or salt form of the active ingredient which is compatiblewith any other ingredients of the pharmaceutical composition, which isnot deleterious to the subject to which the composition is to beadministered.

The formulations of the pharmaceutical compositions described herein maybe prepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with a carrier or one ormore other accessory ingredients, and then, if necessary or desirable,shaping or packaging the product into a desired single- or multi-doseunit.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions that aresuitable for ethical administration to humans, it will be understood bythe skilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and perform such modification with merely ordinary, if any,experimentation. Subjects to which administration of the pharmaceuticalcompositions of the invention is contemplated include, but are notlimited to, humans and other primates, mammals including commerciallyrelevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.

A pharmaceutical composition of the invention may be prepared, packaged,or sold in bulk, as a single unit dose, or as a plurality of single unitdoses. As used herein, a “unit dose” is a discrete amount of thepharmaceutical composition comprising a predetermined amount of theactive ingredient. The amount of the active ingredient is generallyequal to the dosage of the active ingredient which would be administeredto a subject or a convenient fraction of such a dosage such as, forexample, one-half or one-third of such a dosage.

The relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and any additional ingredients in a pharmaceuticalcomposition of the invention will vary, depending upon the identity,size, and condition of the subject treated and further depending uponthe route by which the composition is to be administered. By way ofexample, the composition may comprise between 0.1% and 100% (w/w) activeingredient. In addition to the active ingredient, a pharmaceuticalcomposition of the invention may further comprise one or more additionalpharmaceutically active agents.

Controlled- or sustained-release formulations of a pharmaceuticalcomposition of the invention may be made using conventional technology.

A formulation of a pharmaceutical composition of the invention suitablefor oral administration may be prepared, packaged, or sold in the formof a discrete solid dose unit including, but not limited to, a tablet, ahard or soft capsule, a cachet, a troche, or a lozenge, each containinga predetermined amount of the active ingredient. Other formulationssuitable for oral administration include, but are not limited to, apowdered or granular formulation, an aqueous or oily suspension, anaqueous or oily solution, or an emulsion.

As used herein, an “oily” liquid is one which comprises acarbon-containing liquid molecule and which exhibits a less polarcharacter than water.

A tablet comprising the active ingredient may, for example, be made bycompressing or molding the active ingredient, optionally with one ormore additional ingredients. Compressed tablets may be prepared bycompressing, in a suitable device, the active ingredient in afree-flowing form such as a powder or granular preparation, optionallymixed with one or more of a binder, a lubricant, an excipient, a surfaceactive agent, and a dispersing agent. Molded tablets may be made bymolding, in a suitable device, a mixture of the active ingredient, apharmaceutically acceptable carrier, and at least sufficient liquid tomoisten the mixture. Pharmaceutically acceptable excipients used in themanufacture of tablets include, but are not limited to, inert diluents,granulating and disintegrating agents, binding agents, and lubricatingagents. Known dispersing agents include, but are not limited to, potatostarch and sodium starch glycolate. Known surface active agents include,but are not limited to, sodium lauryl sulphate. Known diluents include,but are not limited to, calcium carbonate, sodium carbonate, lactose,microcrystalline cellulose, calcium phosphate, calcium hydrogenphosphate, and sodium phosphate. Known granulating and disintegratingagents include, but are not limited to, corn starch and alginic acid.Known binding agents include, but are not limited to, gelatin, acacia,pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropylmethylcellulose. Known lubricating agents include, but are not limitedto, magnesium stearate, stearic acid, silica, and talc.

Tablets may be non-coated or they may be coated using known methods toachieve delayed disintegration in the gastrointestinal tract of asubject, thereby providing sustained release and absorption of theactive ingredient. By way of example, a material such as glycerylmonostearate or glyceryl distearate may be used to coat tablets. Furtherby way of example, tablets may be coated using methods described in U.S.Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to formosmotically-controlled release tablets. Tablets may further comprise asweetening agent, a flavoring agent, a coloring agent, a preservative,or some combination of these in order to provide pharmaceuticallyelegant and palatable preparation.

Hard capsules comprising the active ingredient may be made using aphysiologically degradable composition, such as gelatin. Such hardcapsules comprise the active ingredient, and may further compriseadditional ingredients including, for example, an inert solid diluentsuch as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made usinga physiologically degradable composition, such as gelatin. Such softcapsules comprise the active ingredient, which may be mixed with wateror an oil medium such as peanut oil, liquid paraffin, or olive oil.

Liquid formulations of a pharmaceutical composition of the inventionwhich are suitable for oral administration may be prepared, packaged,and sold either in liquid form or in the form of a dry product intendedfor reconstitution with water or another suitable vehicle prior to use.

Liquid suspensions may be prepared using conventional methods to achievesuspension of the active ingredient in an aqueous or oily vehicle.Aqueous vehicles include, for example, water and isotonic saline. Oilyvehicles include, for example, almond oil, oily esters, ethyl alcohol,vegetable oils such as arachis, olive, sesame, or coconut oil,fractionated vegetable oils, and mineral oils such as liquid paraffin.Liquid suspensions may further comprise one or more additionalingredients including, but not limited to, suspending agents, dispersingor wetting agents, emulsifying agents, demulcents, preservatives,buffers, salts, flavorings, coloring agents, and sweetening agents. Oilysuspensions may further comprise a thickening agent. Known suspendingagents include, but are not limited to, sorbitol syrup, hydrogenatededible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gumacacia, and cellulose derivatives such as sodium carboxymethylcellulose,methylcellulose, and hydroxypropylmethylcellulose. Known dispersing orwetting agents include, but are not limited to, naturally-occurringphosphatides such as lecithin, condensation products of an alkyleneoxide with a fatty acid, with a long chain aliphatic alcohol, with apartial ester derived from a fatty acid and a hexitol, or with a partialester derived from a fatty acid and a hexitol anhydride (e.g.,polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylenesorbitol monooleate, and polyoxyethylene sorbitan monooleate,respectively). Known emulsifying agents include, but are not limited to,lecithin and acacia. Known preservatives include, but are not limitedto, methyl, ethyl, or n-propyl-para-hydroxybenzoates, ascorbic acid, andsorbic acid. Known sweetening agents include, for example, glycerol,propylene glycol, sorbitol, sucrose, and saccharin. Known thickeningagents for oily suspensions include, for example, beeswax, hardparaffin, and cetyl alcohol.

Liquid solutions of the active ingredient in aqueous or oily solventsmay be prepared in substantially the same manner as liquid suspensions,the primary difference being that the active ingredient is dissolved,rather than suspended in the solvent. Liquid solutions of thepharmaceutical composition of the invention may comprise each of thecomponents described with regard to liquid suspensions, it beingunderstood that suspending agents will not necessarily aid dissolutionof the active ingredient in the solvent. Aqueous solvents include, forexample, water and isotonic saline. Oily solvents include, for example,almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis,olive, sesame, or coconut oil, fractionated vegetable oils, and mineraloils such as liquid paraffin.

Powdered and granular formulations of a pharmaceutical preparation ofthe invention may be prepared using known methods. Such formulations maybe administered directly to a subject, used, for example, to formtablets, to fill capsules, or to prepare an aqueous or oily suspensionor solution by addition of an aqueous or oily vehicle thereto. Each ofthese formulations may further comprise one or more of dispersing orwetting agent, a suspending agent, and a preservative. Additionalexcipients, such as fillers and sweetening, flavoring, or coloringagents, may also be included in these formulations.

A pharmaceutical composition of the invention may also be prepared,packaged, or sold in the form of oil-in-water emulsion or a water-in-oilemulsion. The oily phase may be a vegetable oil such as olive or arachisoil, a mineral oil such as liquid paraffin, or a combination of these.Such compositions may further comprise one or more emulsifying agentssuch as naturally occurring gums such as gum acacia or gum tragacanth,naturally-occurring phosphatides such as soybean or lecithinphosphatide, esters or partial esters derived from combinations of fattyacids and hexitol anhydrides such as sorbitan monooleate, andcondensation products of such partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. These emulsions may also containadditional ingredients including, for example, sweetening or flavoringagents.

Suppository formulations may be made by combining the active ingredientwith a non-irritating pharmaceutically acceptable excipient which issolid at ordinary room temperature (i.e., about 20° C.) and which isliquid at the rectal temperature of the subject (i.e., about 37° C. in ahealthy human). Suitable pharmaceutically acceptable excipients include,but are not limited to, cocoa butter, polyethylene glycols, and variousglycerides. Suppository formulations may further comprise variousadditional ingredients including, but not limited to, antioxidants andpreservatives.

In yet another embodiment, compositions of the invention may beadministered to the desired location of a subject by a transdermalpatch. A transdermal patch is meant a system capable of delivery of acompound to a subject via the skin, or any suitable external surface,including mucosal membranes, such as those found inside the mouth. Suchdelivery systems generally comprise a flexible backing, an adhesive anda compound retaining matrix, the backing protecting the adhesive andmatrix and the adhesive holding the whole on the skin of the subject. Oncontact with the skin, the compound-retaining matrix delivers thecompound to the skin, the compound then passing through the skin intothe subject's system.

Certain embodiments of the invention provide a pharmaceuticalpreparation/dosage formulation provided in the form of a transdermalpatch and formulated for sustained release formulation, in atherapeutically effective amount sufficient to treat a diseaseassociated with activation of an immune cell (e.g., rheumatoidarthritis) in a patient, wherein the dosage formulation, whenadministered (provided as a patch) to the patient, provides asubstantially sustained dose over at least about 2 hours, 4 hours, 6hours, 8, hours, 12 hours, 20 hours, or at least about 24 hours.

As used herein, “parenteral administration” of a pharmaceuticalcomposition includes any route of administration characterized byphysical breaching of a tissue of a subject and administration of thepharmaceutical composition through the breach in the tissue. Parenteraladministration thus includes, but is not limited to, administration of apharmaceutical composition by injection of the composition, byapplication of the composition through a surgical incision, byapplication of the composition through a tissue-penetrating non-surgicalwound, and the like. In particular, parenteral administration iscontemplated to include, but is not limited to, intravenous,subcutaneous, intraperitoneal, intramuscular, intrasternal injection,bolus injections, and kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteraladministration comprise the active ingredient combined with apharmaceutically acceptable carrier, such as sterile water or sterileisotonic saline. Such formulations may be prepared, packaged, or sold ina form suitable for bolus administration or for continuousadministration. Injectable formulations may be prepared, packaged, orsold in unit dosage form, such as in ampules or in multi-dose containerscontaining a preservative. Formulations for parenteral administrationinclude, but are not limited to, suspensions, solutions, emulsions inoily or aqueous vehicles, pastes, and implantable sustained-release orbiodegradable formulations. Such formulations may further comprise oneor more additional ingredients including, but not limited to,suspending, stabilizing, or dispersing agents. In one embodiment of aformulation for parenteral administration, the active ingredient isprovided in dry (i.e., powder or granular) form for reconstitution witha suitable vehicle (e.g., sterile pyrogen-free water) prior toparenteral administration of the reconstituted composition.

A pharmaceutical composition of the invention may be prepared, packaged,or sold in a formulation suitable for pulmonary administration via thebuccal cavity. Such a formulation may comprise dry particles thatcomprise the active ingredient and that have a diameter in the rangefrom about 0.5 to about 7 nanometers, and preferably from about 1 toabout 6 nanometers. Such compositions are conveniently in the form ofdry powders for administration using a device comprising a dry powderreservoir to which a stream of propellant may be directed to dispersethe powder or using a self-propelling solvent/powder-dispensingcontainer such as a device comprising the active ingredient dissolved orsuspended in a low-boiling propellant in a sealed container. Preferably,such powders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers. Morepreferably, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositionspreferably include a solid fine powder diluent such as sugar and areconveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic or solid anionic surfactant or a solid diluent(preferably having a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may also provide the active ingredient in the form of dropletsof a solution or suspension. Such formulations may be prepared,packaged, or sold as aqueous or dilute alcoholic solutions orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization or atomizationdevice. Such formulations may further comprise one or more additionalingredients including, but not limited to, a flavoring agent such assaccharin sodium, a volatile oil, a buffering agent, a surface activeagent, or a preservative such as methylhydroxybenzoate. The dropletsprovided by this route of administration preferably have an averagediameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful in pulmonary deliveryare also useful in intranasal delivery of a pharmaceutical compositionof the invention.

Another formulation suitable for intranasal administration is a coarsepowder comprising the active ingredient and having an average particlefrom about 0.2 to 500 micrometers. Such a formulation is administered inthe manner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close to the nares.

Formulations suitable for nasal administration may, for example,comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) ofthe active ingredient, and may further comprise one or more of theadditional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged,or sold in a formulation suitable for buccal administration. Suchformulations may, for example, be in the form of tablets or lozengesmade using conventional methods, and may, for example, contain 0.1 to20% (w/w) active ingredient, the balance comprising an orallydissolvable or degradable composition and, optionally, one or more ofthe additional ingredients described herein. Alternately, formulationssuitable for buccal administration may comprise a powder or anaerosolized or atomized solution or suspension comprising the activeingredient. Such powdered, aerosolized, or aerosolized formulations,when dispersed, preferably have an average particle or droplet size inthe range from about 0.1 to about 200 nanometers, and may furthercomprise one or more of the additional ingredients described herein.

As used herein, “additional ingredients” include, but are not limitedto, one or more of the following: excipients; surface active agents;dispersing agents; inert diluents; granulating and disintegratingagents; binding agents; lubricating agents; sweetening agents; flavoringagents; coloring agents; preservatives; physiologically degradablecompositions such as gelatin; aqueous vehicles and solvents; oilyvehicles and solvents; suspending agents; dispersing or wetting agents;emulsifying agents, demulcents; buffers; salts; thickening agents;fillers; emulsifying agents; antioxidants; antibiotics; antifungalagents; stabilizing agents; and pharmaceutically acceptable polymeric orhydrophobic materials. Other “additional ingredients” which may beincluded in the pharmaceutical compositions of the invention are knownin the art and described, for example in Genaro, ed. (1985, Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa.), which isincorporated herein by reference.

Typically, dosages of the compound of the invention which may beadministered to a subject, preferably a human, will vary depending uponany number of factors, including but not limited to, the type of animaland type of disease state being treated, the age of the subject and theroute of administration. The compound can be administered to a subjectas frequently as several times daily, or it may be administered lessfrequently, such as once a day, once a week, once every two weeks, oncea month, or even less frequently, such as once every several months oreven once a year or less. The frequency of the dose will be readilyapparent to the skilled artisan and will depend upon any number offactors, such as, but not limited to, the type and severity of thedisease being treated, the type and age of the subject, and the like.

Kit and Probes

In some embodiments, the present invention also includes pharmaceuticalkits and/or research probes useful, for example, in the treatment orprevention of HDACs associated diseases or disorders such as cancer,neurodegenerative diseases and pathological autoimmune response. In oneembodiment, the kit includes a compound of the present invention. Suchkits can further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, as will be readily apparent to those skilled inthe art. Instructions, either as inserts or as labels, indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, can also beincluded in the kit.

In some embodiments, the present invention also includes probescomprising a compound of the invention, useful, for example, in thetreatment or prevention of HDACs associated diseases or disorders suchas cancer, neurodegenerative diseases and pathological autoimmuneresponse, or in the imaging or theragnostics approaches to HDACsassociated diseases or disorders such as cancer, neurodegenerativediseases and pathological autoimmune response. In one embodiment, aprobe comprises a compound of the invention further conjugated to aradiolabeled moiety, a fluorescent labeled moiety, or biotin. Anynumbers of linkers known in the art can be used for conjugation. Inanother embodiment, no linker is necessary for conjugation. In someembodiments, a conjugated probe including a compound of the invention isused for research, diagnostic and therapeutic purposes.

In one aspect, the invention provides methods comprising the use oftheragnostics, or theranostics, further comprising a compound of theinvention. Theragnostics, or theranostics, are compounds, formulationsand compositions, capable of functioning as both therapeutic agents anddiagnostic agents. For example, a probe of the invention can inhibit ormodulate the activity of one or more HDACs, and at the same time providefor the possibility of imaging its distribution in a cell, tissue,organ, or entire body. Modern approaches to theragnostics, ortheranostics, have been described by Xie et al., 2010, Adv Drug DelivRev, 62(11): 1064-1079, and Pene et al., 2009, Crit Care Med., 37(1Suppl):S50-8, descriptions incorporated herein in their entirety.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is further described in detail by reference to thefollowing experimental examples. These examples are provided forpurposes of illustration only, and are not intended to be limitingunless otherwise specified. Thus, the invention should in no way beconstrued as being limited to the following examples, but rather, shouldbe construed to encompass any and all variations which become evident asa result of the teaching provided herein.

The experiments disclosed herein were designed to generate novel HDACsinhibitors, both pan-inhibitors of several or all classes of HDACs, andselective inhibitors between and/or within classes. These inhibitors canserve as novel therapeutic agents for HDACs related diseases anddisorders. The materials and methods employed in these experiments arenow described.

Example 1: Synthesis of Compounds of the Invention

The compounds of the invention can be prepared by a person skilled inthe art of synthetic organic chemistry once armed with the teachingsherein. The person skilled in the art knows how to select and implementappropriate synthetic routes. Suitable synthetic methods may beidentified by reference to the literature describing synthesis ofanalogous compounds, and then performing the synthesis of the desiredcompound following the route used for the analogous compounds, modifyingthe starting materials, reagents, and reaction conditions as appropriateto synthesizing any particular desired compounds. In addition, referencemay be made to sources such as Comprehensive Organic Synthesis, Ed. B.M. Trost and I. Fleming (Pergamon Press 1991), Comprehensive OrganicFunctional Group Transformations, Ed. A. R. Katritzky, O. Meth Cohn, andC. W. Rees (Pergamon Press, 1996), Comprehensive Organic FunctionalGroup Transformations II, Ed. A. R. Katritzky and R. J. K. Taylor(Editor) (Elsevier, 2nd Edition, 2004), Comprehensive HeterocyclicChemistry, Ed. A. R. Katritzky and C. W. Rees (Pergamon Press, 1984),and Comprehensive Heterocyclic Chemistry II, Ed. A. R. Katritzky, C. W.Rees, and E. F. V. Scriven (Pergamon Press, 1996), the entiredisclosures of which are incorporated herein by reference.

In one embodiment of the invention, the starting materials andintermediates required for the synthesis may be obtained from commercialsources or synthesized according to methods known to those skilled inthe art. In various embodiments, a compound of the invention can besynthesized according to Scheme 1, Scheme 2, Scheme 3, Scheme 4, or anyvariations thereof apparent to one skilled in the art.

Compound Example 1.N-(2-amino-5-(thiophen-2-yl)phenyl)-4-((6-oxo-2,5-diazaspiro[3.5]nonan-5-yl)methyl)benzamide

Compound Example 1 was synthesized according to Scheme 1. ¹HNMR (400MHz, DMSO-d6): δ 9.70 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.48 (s, 1H),7.24-7.35 (m, 5H), 7.05 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.16 (s, 2H),4.94 (s, 2H), 3.63 (d, J=7.6 Hz, 2H), 3.60 (d, J=7.6 Hz, 2H), 2.38 (t,J=6.4 Hz, 2H), 2.18 (m, 2H), 1.73 (m, 2H). LC-MS showed a single peakwith purity >95% based on UV absorption at 254 nm. MS: C₂₅H₂₆N₄O₂S.Calculated (M+H): 447, obtained MS: 447.

Compound Example 2.N-(2-amino-5-(thiophen-2-yl)phenyl)-4-((2-oxo-1,8-diazaspiro[4.5]decan-1-yl)methyl)benzamide

Compound Example 2 was synthesized according to Scheme 1. ¹HNMR(DMSO-d6, 400 MHz): δ, 9.84 (s, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.48 (s,1H), 7.41 (d, J=8.0 Hz, 2H), 7.35 (d, J=4.8 Hz, 1H), 7.28-7.30 (m, 1H),7.24 (d d, J=3.2 Hz, 1H), 7.03-7.06 (m, 1H), 6.81 (d, J=8.0 Hz, 1H),5.20 (s, 2H). 4.43 (s, 2H), 3.13-3.16 (m, 2H), 2.84-2.90 (m, 2H),2.40-2.44 (m, 2H), 2.12-2.20 (m, 2H), 2.03-2.07 (m, 2H), 1.42-1.45 (m,2H). LC-MS showed a single peak with purity >95% based on UV absorptionat 254 nm. MS: C₂₆H₂₈N₄O₂S. Calculated (M+H): 461, obtained MS: 461.

Compound Example 3.N-(2-amino-4-fluorophenyl)-4-((6-oxo-2,5-diazaspiro[3.5]nonan-5-yl)methyl)benzamide

Compound Example 3 was synthesized according to Scheme 1. ¹HNMR (400MHz, DMSO-d6): δ 9.54 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0Hz, 2H), 7.11 (t, J=7.4 Hz, 1H), 6.52-6.55 (dd, 1H), 6.35 (t, J=2.4 Hz,1H), 5.22 (s, 2H), 4.93 (s, 2H), 3.68-3.71 (m, 2H), 3.27-3.34 (m, 4H),2.38 (t, J=6.4 Hz, 2 Hz), 2.19-2.20 (m, 1H), 1.72-1.75 (m, 2H). LC-MSshowed a single peak with purity >95% based on UV absorption at 254 nm.MS: C₂₁H₂₃FN₄O₂. Calculated (M+H): 383, obtained MS: 383.

Compound Example 4.N-(2-amino-5-(thiophen-2-yl)phenyl)-6-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)nicotinamide

Compound Example 4 was synthesized according to Scheme 2. ¹HNMR (400MHz, 10% D20 in DMSO-d6): δ 8.99 (s, 1H), 8.44-8.42 (m, 1H), 8.24 (d,J=8.8 Hz, 1H), 7.61 (s, 1H), 7.54-7.52 (m, 1H), 7.48 (d, J=5.2 Hz, 1H),7.42 (d, J=3.2 Hz, 1H), 7.18-7.13 (m, 2H), 4.25 (s, 0.6H), 4.13 (s,1.4H), 3.50-3.47 (m, 2H), 3.29-3.18 (m, 2H), 2.86 (s, 3H), 2.37-2.30 (m,2H), 2.20-2.13 (m, 2H). LC-MS showed a single peak with purity >95%based on UV absorption at 254 nm. MS: C₂₄H₂₅N₅O₃S. Calculated (M+H):464, obtained MS: 464.

Compound Example 5.N-(4-amino-4′-fluoro-[1,1′-biphenyl]-3-yl)-6-(2-oxo-1,8-dioxa-3-azaspiro[4.5]decan-3-yl)nicotinamide

Compound Example 5 was synthesized according to Scheme 2. 1HNMR (400MHz, DMSO-d6): δ 9.84 (s, 1H), 8.98 (s, 1H), 8.38-8.45 (m, 1H), 8.22 (s,1H), 7.56-7.62 (m, 2H), 7.50 (d, J=0.42 Hz, 1H), 7.30-7.34 (m, 1H), 7.22(t, J=8.80 Hz, 2H), 6.86 (d, J=8.40 Hz, 1H), 5.18 (s, 2H), 4.09 (s, 2H),3.69-3.74 (m, 4H), 1.86-2.00 (m, 4H). LC-MS showed a single peak withpurity >95% based on UV absorption at 254 nm. MS: C₂₅H₂₃FN₄O₄.Calculated (M+H): 463, obtained MS: 463.

Compound Example 6.N-(2-amino-5-(thiophen-2-yl)phenyl)-6-(3-oxo-2,9-diazaspiro[5.5]undecan-2-yl)nicotinamide

Compound Example 6 was synthesized according to Scheme 3. ¹H-NMR (400MHz, CD₃OD): δ 9.04 (s, 1H), 8.35 (dd, J=0.5, 2.2 Hz, 1H), 7.95 (d,J=2.1 Hz, 1H), 7.51 (d, J=0.2 Hz, 1H), 7.37 (dd, J=0.5, 2.1 Hz, 1H),7.24 (m, 2H), 7.03 (t, J=1.0 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 3.95 (s,2H), 2.86 (m, 4H), 2.64 (t, J=1.7 Hz, 2H), 1.87 (t, J=1.8 Hz, 2H), 1.61(t, J=1.5 Hz, 4H). LC-MS showed a single peak with purity >95% based onUV absorption at 254 nm. MS: C₂₅H₂₇N₅O₂S. Calculated (M+H): 462,obtained MS: 462.

Compound Example 7.N-(2-amino-4-fluorophenyl)-6-(3-oxo-2,9-diazaspiro[5.5]undecan-2-yl)nicotinamide

Compound Example 7 was synthesized according to Scheme 3. ¹H-NMR (400MHz, CD₃OD): δ 8.91 (s, 1H), 8.24 (dd, J=0.5, 2.2 Hz, 1H), 7.89 (m, 1H),7.04 (dd, J=1.5, 2.2 Hz, 1H), 6.51 (dd, J=0.5, 2.7 Hz, 1H), 6.34 (dd,J=0.6, 2.1 Hz, 1H), 5.25 (t, J=1.2 Hz, 1H), 3.93 (m, 2H), 3.12 (m, 2H),2.56 (t, J=1.7 Hz, 2H), 1.94 (m, 2H), 1.84 (t, J=1.8 Hz, 2H), 1.76 (t,J=1.5 Hz, 4H). LC-MS showed a single peak with purity >95% based on UVabsorption at 254 nm. MS: C₂₁H₂₄FN₅O₂. Calculated (M+H): 398, obtainedMS: 398.

Example 2: Dose Dependent Inhibition of HDAC Compounds Prepared inEnzymatic Assays

The results described below demonstrate dose dependent inhibition ofHDAC compounds prepared in enzymatic assays, and the IC50 values ofsynthesized and reference compounds in HDAC Enzymatic Assays. Incubationtime for HDAC1/2 is 120 min, and 10 min for other HDACs.

Materials and Methods: Enzymes

Human HDAC1 (GenBank Accession No. NM_004964), full-length with aC-terminal His-tag and a C-terminal FLAG-tag, MW=56 kDa, was expressedin a baculovirus expression system.

Human HDAC2 (GenBank Accession No. NM_001527), full-length with aC-terminal His-tag, MW=56 kDa, was expressed in a baculovirus expressionsystem.

Complex of human HDAC3 (GenBank Accession No. NM_003883), full-lengthwith a C-terminal His tag, MW=49.7 kDa, and human NCOR2 (amino acid395-489) (GenBank Accession No. NM_006312), N-terminal GST tag, MW=37.6kDa, was co-expressed in a baculovirus expression system.

Human HDAC4 (GenBank Accession No. NM_006037), amino acids 627-1085 witha N-terminal GST tag, MW=75.2 kDa, was expressed in a baculovirusexpression system.

Human HDAC5 (GenBank Accession No. NM_005474), full-length with anN-terminal GST tag, MW=150 kDa, was expressed in a baculovirusexpression system.

Recombinant human HDAC6 (GenBank Accession No. BC069243), full-length,MW=180 kDa, was expressed by baculovirus in Sf9 insect cells using anN-terminal GST tag.

Human HDAC7 (GenBank Accession No. AY302468), (a.a. 518-end) with anN-terminal GST tag, MW=78 kDa, was expressed in a baculovirus expressionsystem.

Human HDAC8 (GenBank Accession No. NM_018486), full-length with aC-terminal His tag, MW=46.4 kDa, was expressed in a baculovirusexpression system.

Human HDAC9 (GenBank Accession No. NM_178423), amino acids 604-1066 witha C-terminal His tag, MW=50.7 kDa, was expressed in a baculovirusexpression system.

Human HDAC10 (a.a. 1-481), GenBank Accession No. NM_032019 with aN-terminal GST tag and a C-terminal His tag, MW=78 kDa, was expressed ina baculovirus expression system.

Human HDAC11 (full length) (GenBank Accession No. NM_024827) with aN-terminal GST tag, MW=66 kDa, was expressed in a baculovirus expressionsystem.

Human SIRT1 (Sirtuin 1, hSir2SIRT1)(GenBank Accession No. NM012238):Full length, MW=82 kDa, expressed in E. coli.

Human SIRT2 (Sirtuin 2, hSir2SIRT2) (GenBank Accession No. NM_012237):Full length, MW=43 kDa, expressed in E. coli.

Human SIRT3 (Sirtuin 3) (GenBank Accession No. NM_012239): Amino acids102-399 (catalytically active), MW=32.7 kDa, expressed in E. coli.

Human SIRT5 (Sirtuin 5) (GenBank Accession No. NM_012241 (isoform 1);residues 37-310, MW=32.3 kDa) expressed in E. coli with an N-terminalHis-tag).

The substrate RHKKAc-AMC, RHKAcKAc-AMC and AcK(trifluoroacetyl)-AMC weresynthesized by Biomer.

ACY-1215, SAHA, Tubastatin A and Trichostatin A (TSA) was purchased fromSelleckchem. TMP269 was purchased from MedKoo Biosciences. Nicotinamideadenine dinucleotide (NAD) was purchased from Tocris.

Materials and Methods: Biochemical Assay Procedure

-   -   I. Compound handling: Testing compounds were dissolved in 100%        DMSO to a specific concentration. The serial dilution was        conducted by epMotion 5070 in DMSO.    -   II. HDAC reaction buffer: 50 mM Tris-HCl, pH8.0, 137 mM NaCl,        2.7 mM KCl, and 1 mM MgCl2, Added fresh: 1 mg/ml BSA, 1% DMSO.    -   III. Substrate: Fluorogenic HDAC General Substrate for HDAC1, 2,        3, 6, 10, 11 ans Sirt1, 2 and 3: Arg-His-Lys-Lys(Ac); HDAC8 only        substrate: Arg-His-Lys(Ac)-Lys(Ac); Class2A Substrate (HDAC4, 5,        7 and 9): Acetyl-Lys(trifluoroacetyl)-AMC; Sirt5 substrate:        Ac-Lys(succinyl)-AMC.    -   IV. General Reaction Procedure: (Standard IC50 determination)        -   a. Delivered 2× enzyme in wells of reaction plate except No            Enzyme (No En) control wells. Add buffer in No En wells.        -   b. Delivered compounds in 100% DMSO into the enzyme mixture            by Acoustic technology (Echo550; nanoliter range). Spin down            and pre-incubation.        -   c. Delivered 2× Substrate Mixture (Fluorogenic HDAC            Substrate and co-factor (500 μM of Nicotinamide adenine            dinucleotide (NAD⁺) in all Sirt assay) in all reaction wells            to initiate the reaction. Spin and shake.        -   d. Incubated for 1-2 hr. at 30° C. with seal.        -   e. Added Developer with Trichostatin A (or TMP269 or NAD⁺)            to stop the reaction and to generate fluorescent color.        -   f. Fluorescence was read (excitatory, 360; emission, 460)            using the EnVision Multilabel Plate Reader (Perkin Elmer)        -   g. Endpoint reading was taken for analysis after the            development reaches plateau.    -   V. Data Analysis: The percentages of enzyme activity (relative        to DMSO controls) and IC50 values were calculated using the        GraphPad Prism 4 program based on a sigmoidal dose-response        equation.

The inhibitory activities of HDAC of compounds of the invention weredetermined using biochemical HDAC assays. The data are summarized in theTable 1. Compounds were tested at the indicated doses in the biochemicalassays of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9,HDAC10, or HDAC11 enzyme. The curve fit and IC50 values were calculatedusing the GraphPad Prism 4 program based on a sigmoidal dose-responseequation.

TABLE 1 Biochemical HDAC assays data for selected compounds. HDAC1 HDAC2HDAC3 HDAC6 HDAC8 cmpd (μM) (μM) (μM) (μM) (μM) Example 1 0.006 0.0613 >20 >20 Hd Example 2 0.014 0.146 >20 >20 >20 F4 Example 3 20 11.81.9 >10 >10 He Example 4 0.007 0.064 17.4 >20 >20 Fa Example 5 0.0230.115 >20 >20 >20 Fb Example 6 0.085 0.61 >20 >20 >20 F1

Example 3: Modulation of a-Tubulin Acetylation by Compound Example 1 andCompound Example 4 in PC-3 Cells

PC-3 cells were treated with the indicated concentrations of CompoundsExample 1 and Example 4 or 24 hours as depicted in FIG. 1. The wholecell lysates were subjected to Western blot analyses withanti-Acetylated-tubulin antibody. The blots were then re-probed withanti-alpha-tubulin antibody. FIG. 1 depicts an image of the Westernblot.

Example 4: Synthesis of Compounds of Formulae I-A and I-B

The compounds of the invention can be prepared by a person skilled inthe art of synthetic organic chemistry once armed with the teachingsherein. The person skilled in the art knows how to select and implementappropriate synthetic routes. Suitable synthetic methods may beidentified by reference to the literature describing synthesis ofanalogous compounds, and then performing the synthesis of the desiredcompound following the route used for the analogous compounds, modifyingthe starting materials, reagents, and reaction conditions as appropriateto synthesizing any particular desired compounds. In addition, referencemay be made to sources such as Comprehensive Organic Synthesis, Ed. B.M. Trost and I. Fleming (Pergamon Press 1991), Comprehensive OrganicFunctional Group Transformations, Ed. A. R. Katritzky, O. Meth Cohn, andC. W. Rees (Pergamon Press, 1996), Comprehensive Organic FunctionalGroup Transformations II, Ed. A. R. Katritzky and R. J. K. Taylor(Editor) (Elsevier, 2nd Edition, 2004), Comprehensive HeterocyclicChemistry, Ed. A. R. Katritzky and C. W. Rees (Pergamon Press, 1984),and Comprehensive Heterocyclic Chemistry II, Ed. A. R. Katritzky, C. W.Rees, and E. F. V. Scriven (Pergamon Press, 1996), the entiredisclosures of which are incorporated herein by reference.

In one embodiment of the invention, the starting materials andintermediates required for the synthesis may be obtained from commercialsources or synthesized according to methods known to those skilled inthe art. In various embodiments, a compound of the invention can besynthesized according to Scheme 5, Scheme 6, Scheme 7, Scheme 8, or anyvariations thereof apparent to one skilled in the art.

Compound Example 8.N-hydroxy-4-((3-oxospiro[isoindoline-1,2′-[1.3]dioxolan]-2-yl)methyl)benzamide

Compound Example 8 was synthesized according to Scheme 5. ¹H-NMR (400MHz, DMSO-d6+10% D2O): δ 7.72-7.36 (m, 5H), 7.38 (d, J=2.0 Hz, 2H), 4.58(s, 2H), 4.32-4.22 (m, 4H). LC-MS showed a single peak with purity >95%based on UV absorption at 254 nm. MS: C18H16N2O5. Calculated (M+H): 341,obtained MS: 341.

Compound Example 9.N-hydroxy-4-((2′-oxo-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-1′-yl)methyl)benzamide

Compound Example 9 was synthesized according to Scheme 6. ¹H-NMR (400MHz, DMSO-d6+10% D2O): δ 8.10 (d, J=7.6 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H),7.65-7.71 (m, 4H), 7.37 (d, J=8.0 Hz, 2H), 4.78 (s, 2H), 3.44 (d, J=8.0Hz, 4H), 2.39-2.42 (m, 2H), 1.57 (d, J=13.6 Hz, 2H). LC-MS showed asingle peak with purity >95% based on UV absorption at 254 nm. MS:C19H18N2O4. Calculated (M+H): 339, obtained MS: 339.

Compound Example 10.N-hydroxy-4-((3-oxospiro[isoindoline-1,4′-piperidin]-2-yl)methyl)benzamide

Compound Example 10 was synthesized according to Scheme 7. ¹H-NMR (400MHz, CDCl3): δ 7.72 (d, J=7.2 Hz, 2H), 7.32-7.37 (m, 3H), 7.18 (t, J=7.2Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 6.68 (d, J=7.2 Hz, 1H), 4.96 (s, 1H),4.25 (t, J=6.4 Hz, 2H), 4.09 (d, J=8.4 Hz, 1H), 3.98 (d, J=8 Hz, 1H),3.69 (br, 0.5H), 3.11 (br, 0.51H), 2.56-2.62 (m, 1H), 2.18-2.24 (m, 1H),1.46 (br, 1H). LC-MS showed a single peak with purity >95% based on UVabsorption at 254 nm. MS: C₂₀H₂₁N₃O₃. Calculated (M+H): 352, obtainedMS: 352.

Compound Example 11.2-(4-(hydroxycarbamoyl)benzyl)-N,N-dimethyl-3-oxospiro[isoindobne-1,4′-piperidine]-1′-carboxamide

Compound Example 11 was synthesized according to Scheme 8. LC-MS showeda single peak with purity >95% based on UV absorption at 254 nm. MS:C23H26N4O4. Calculated (M+H): 423, obtained MS: 423.

Compound Example 12.4-((r-cyclopropyl-3-oxospiro[isoindoline-1,4′-piperidin]-2-yl)methyl)-N-hydroxybenzamide

Compound Example 12 was synthesized according to Scheme 8. LC-MS showeda single peak with purity >95% based on UV absorption at 254 nm. MS:C23H25N3O3. Calculated (M+H): 392, obtained MS: 392.

Compound Example 13.4-((1′-(cyclopropanecarbonyl)-3-oxospiro[isoindoline-1,4′-piperidin]-2-yl)methyl)-N-hydroxybenzamide

Compound Example 13 was synthesized according to Scheme 8. LC-MS showeda single peak with purity >95% based on UV absorption at 254 nm. MS:C24H25N3O4. Calculated (M+H): 420, obtained MS: 420.

Example 5: Dose Dependent Inhibition of HDAC Compounds Prepared inEnzymatic Assays

The results described below demonstrate dose dependent inhibition ofHDAC compounds prepared in enzymatic assays, and the IC50 values ofsynthesized and reference compounds in HDAC Enzymatic Assays. Incubationtime for HDAC1/2 is 120 min, and 10 min for other HDACs.

Materials and Methods: Enzymes

Human HDAC1 (GenBank Accession No. NM_004964), full-length with aC-terminal His-tag and a C-terminal FLAG-tag, MW=56 kDa, was expressedin a baculovirus expression system.

Human HDAC2 (GenBank Accession No. NM_001527), full-length with aC-terminal His-tag, MW=56 kDa, was expressed in a baculovirus expressionsystem.

Complex of human HDAC3 (GenBank Accession No. NM_003883), full-lengthwith a C-terminal His tag, MW=49.7 kDa, and human NCOR2 (amino acid395-489) (GenBank Accession No. NM_006312), N-terminal GST tag, MW=37.6kDa, was co-expressed in a baculovirus expression system.

Human HDAC4 (GenBank Accession No. NM_006037), amino acids 627-1085 witha N-terminal GST tag, MW=75.2 kDa, was expressed in a baculovirusexpression system.

Human HDAC5 (GenBank Accession No. NM_005474), full-length with anN-terminal GST tag, MW=150 kDa, was expressed in a baculovirusexpression system.

Recombinant human HDAC6 (GenBank Accession No. BC069243), full-length,MW=180 kDa, was expressed by baculovirus in Sf9 insect cells using anN-terminal GST tag.

Human HDAC7 (GenBank Accession No. AY302468), (a.a. 518-end) with anN-terminal GST tag, MW=78 kDa, was expressed in a baculovirus expressionsystem.

Human HDAC8 (GenBank Accession No. NM_018486), full-length with aC-terminal His tag, MW=46.4 kDa, was expressed in a baculovirusexpression system.

Human HDAC9 (GenBank Accession No. NM_178423), amino acids 604-1066 witha C-terminal His tag, MW=50.7 kDa, was expressed in a baculovirusexpression system.

Human HDAC10 (a.a. 1-481), GenBank Accession No. NM_032019 with aN-terminal GST tag and a C-terminal His tag, MW=78 kDa, was expressed ina baculovirus expression system.

Human HDAC11 (full length) (GenBank Accession No. NM_024827) with aN-terminal GST tag, MW=66 kDa, was expressed in a baculovirus expressionsystem.

Human SIRT1 (Sirtuin 1, hSir2SIRT1) (GenBank Accession No. NM012238):Full length, MW=82 kDa, expressed in E. coli.

Human SIRT2 (Sirtuin 2, hSir2SIRT2) (GenBank Accession No. NM_012237):Full length, MW=43 kDa, expressed in E. coli.

Human SIRT3 (Sirtuin 3) (GenBank Accession No. NM_012239): Amino acids102-399 (catalytically active), MW=32.7 kDa, expressed in E. coli.

Human SIRT5 (Sirtuin 5) (GenBank Accession No. NM_012241 (isoform 1);residues 37-310, MW=32.3 kDa) expressed in E. coli with an N-terminalHis-tag).

The substrate RHKKAc-AMC, RHKAcKAc-AMC and AcK(trifluoroacetyl)-AMC weresynthesized by Biomer.

ACY-1215, SAHA, Tubastatin A and Trichostatin A (TSA) was purchased fromSelleckchem. TMP269 was purchased from MedKoo Biosciences. Nicotinamideadenine dinucleotide (NAD) was purchased from Tocris.

Materials and Methods: Biochemical Assay Procedure

-   -   I. Compound handling: Testing compounds were dissolved in 100%        DMSO to a specific concentration. The serial dilution was        conducted by epMotion 5070 in DMSO.    -   II. HDAC reaction buffer: 50 mM Tris-HCl, pH8.0, 137 mM NaCl,        2.7 mM KCl, and 1 mM MgCl2, Added fresh: 1 mg/ml BSA, 1% DMSO.    -   III. Substrate: Fluorogenic HDAC General Substrate for HDAC1, 2,        3, 6, 10, 11 ans Sirt1, 2 and 3: Arg-His-Lys-Lys(Ac); HDAC8 only        substrate: Arg-His-Lys(Ac)-Lys(Ac); Class2A Substrate (HDAC4, 5,        7 and 9): Acetyl-Lys(trifluoroacetyl)-AMC; Sirt5 substrate:        Ac-Lys(succinyl)-AMC.    -   IV. General Reaction Procedure: (Standard IC50 determination)        -   a. Delivered 2× enzyme in wells of reaction plate except No            Enzyme (No En) control wells. Add buffer in No En wells.        -   b. Delivered compounds in 100% DMSO into the enzyme mixture            by Acoustic technology (Echo550; nanoliter range). Spin down            and pre-incubation.        -   c. Delivered 2× Substrate Mixture (Fluorogenic HDAC            Substrate and co-factor (500 mM of Nicotinamide adenine            dinucleotide (NAD⁺) in all Sirt assay) in all reaction wells            to initiate the reaction. Spin and shake.        -   d. Incubated for 1-2 hr. at 30° C. with seal.        -   e. Added Developer with Trichostatin A (or TMP269 or NAD⁺)            to stop the reaction and to generate fluorescent color.        -   f. Fluorescence was read (excitatory, 360; emission, 460)            using the EnVision Multilabel Plate Reader (Perkin Elmer)        -   g. Endpoint reading was taken for analysis after the            development reaches plateau.    -   V. Data Analysis: The percentages of enzyme activity (relative        to DMSO controls) and IC50 values were calculated using the        GraphPad Prism 4 program based on a sigmoidal dose-response        equation.

The inhibitory activities of HDAC compounds were determined usingbiochemical HDAC assays and data are summarized in Table 2. Compoundswith indicated doses were tested in the biochemical assays of HDAC1,HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC 8, HDAC9, HDAC10, orHDAC11 enzyme. The curve fit and IC50 values were calculated using theGraphPad Prism 4 program based on a sigmoidal dose-response equation.

TABLE 2 Biochemical HDAC assay data for selected compounds of FormulaI-A and I-B. Compound HDAC1 HDAC2 HDAC3 HDAC4 HDAC5 HDAC6 HDAC7 HDAC8HDAC9 HDAC10 HDAC11 Example (μM) (μM) (μM) (μM) (μM) (μM) (μM) (μM) (μM)(μM) (μM) 8 8.0 >10 >10 0.029 0.40 9 9.1 17.2 21 0.0045 1.92 10 6.0 >107.0 0.205 0.710 11 >10 >10 >10 5.0 1.55 0.035 0.85 0.52 3.2 >10 4.112 >10 >10 9.26 >10 >10 0.026 3.1 1.2 6.9 >10 3.6

Example 6: Modulation of a-Tubulin Acetylation by Some of Inhibitors inPC-3 Cells

PC-3 cells were treated with the indicated concentrations of CompoundExamples 8, 10, 11, and 13 for 24 hours as depicted in FIG. 2. The wholecell lysates were subjected to Western blot analyses withanti-Acetylated-tubulin antibody (FIG. 2). The blots were then re-probedwith anti-alpha-tubulin antibody.

Example 7: In Vivo Pharmacokinetics Studies ofN-(2-amino-5-(thiophen-2-yl)phenyl)-6-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)nicotinamidein Mice

In vivo PK (pharmacokinetics) studies were run at Scripps Florida DMPKCore facility. Mouse plasma PK data was obtained using Compound Example4(N-(2-amino-5-(thiophen-2-yl)phenyl)-6-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)nicotinamide)

Materials and Methods. Compound Example 4 Mouse Plasma PK:

Dose: 1 mg/kg intravenous (IV) and 7 mg/kg oral dosage (PO)

Formulation: 0.1 mg/mL IV and 1 mg/mL PO solution in 10/10/80DMSO/Tween80/Water

Mice Info: Male C57 B1/6J

Results.

Plasma PK were evaluated in mice after administration of CompoundExample 4. Following IV administration, the PK properties show a goodhalf-life (T_(1/2)) of 1.2 h, high AUC (˜ 7.3 μM·h), low clearance, andlow volume (Table 3). The properties are also fair by oral dosing, withgood half-life (1.9 h) and AUC (area under curve) (˜16 μM·h), and areasonable bioavailability (% F) of 31% (Table 4). Maximal half-life(T_(max)), maximal concentration (C_(max)), observed clearance (Cl_obs),mean residential time (MRT), and volume of distribution (Vss_obs) werealso quantified (Tables 3 and 4).

TABLE 3 Mouse plasma PK data after IV administration of Compound Example4. Mouse-1 Mouse-2 Mouse-3 Average T_(1/2) (hr) 0.86 1.33 1.28 1.16T_(max) (hr) 0.08 0.08 0.08 0.08 C_(max) (ng/mL) 1560 2490 2040 2030C_(max) (μM) 3.37 5.38 4.41 4.38 AUC_(last) 212187 175879 219951 202672(min * ng/mL) AUC_(last) 7.64 6.33 7.92 7.30 (μM · hr) AUC_(INF)_obs212819 177722 224191 204911 (min * ng/mL) AUC 0.30 1.04 1.89 1.08 (%Extrap) Cl_obs 4.70 5.63 4.46 4.93 (mL/min/kg) MRT_(INF)_obs 1.76 1.741.97 1.82 (hr) Vss_obs 0.50 0.59 0.53 0.54 (L/kg)

TABLE 4 Mouse plasma PK data after oral administration of CompoundExample 4. Mouse-1 Mouse-2 Mouse-3 Average T_(1/2) (hr) 1.65 2.25 1.781.90 T_(max) (hr) 1.00 1.00 1.00 1.00 C_(max) (ng/mL) 3200 1930 23502493 C_(max) (μM) 6.91 4.17 5.08 5.39 AUC_(last) 654948 303573 369340442620 (min * ng/mL) AUC_(last) 23.58 10.93 13.30 15.93 (μM · hr)AUC_(INF)_obs 690882 335315 388640 471613 (min * ng/mL) AUC (% 5.20 9.474.97 6.54 Extrap) Cl_obs 10.13 20.88 18.01 16.34 (mL/min/kg) % F N/A N/AN/A 31%

Example 8: Brain Exposure Experiments UsingN-(2-amino-5-(thiophen-2-yl)phenyl)-6-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl(nicotinamide(Compound Example 4)

Brain exposure experiments were performed wherein mice were exposed toCompound Example 4 at an IV dosage of 1 mg/kg (Table 5). The resultsshowed that Compound Example 4 expressed very low brain penetration 1hour after exposure.

TABLE 5 Brain exposure experiments of Compound Example 4 in mice PlasmaBrain Mouse # (ng/mL) μM (ng/mL) μM 7 1660 3.59 61.9 0.13 8 1030 2.22 00.00 9 1620 3.50 73 0.16 Average 1436.7 3.10 67.5 0.15

Example 9: Determination of the Efficacy of Y-5Fa and Compound Example 4in the HCT-116 Xenograft Model Using Female CD-1 Nude Mice

IX.a Animal model background. A mouse HCT-116 xenograft tumor model wasused to evaluate the efficacy of Compound Example 4.

IX.b Animal Testing Details.

III.b1 Animal

A. Species: Mouse

B. Strain: CD-I nude

C. Source: Charles River Laboratories

D. Age at Initiation of Treatment: Approximately 6 to 7 weeks of age

E. Weight at Initiation of Treatment: Approximately 15 to 20 grams.

F. Number and Sex: 40 females for each compound.

G. Identification: Individual caged identified by cage card.

H. Acclimation: For at least three days.

I. Randomization: Based on tumor volume. Only healthy animals areincluded.

IX.b2 Husbandry

A. Housing: Animals are housed of two per cage in plastic boxes.

B. Diet: Certified Rodent Diet #5002 (LabDiet) ad libitum, unlessotherwise specified.

C. Water: Ad libitum.

D. Contaminants: There are no known contaminants in the diet or water atlevels that might interfere with this study.

E. Environment: Environmental controls for the animal room are set tomaintain 18 to 26° C., a relative humidity of 30 to 70%, a minimum of 10air changes/hour, and a 12-hour light/12-hour dark cycle.

IX.b3 Vehicle Articles

A. Identification: 40% PEG-400 (v/v), 25% HP(3CD (w/v) and 35% PurifiedWater

B. Lot Numbers: The lot numbers are maintained in the raw data.

C. Purity: The lot number are recorded as provided by the manufacturer.

D. Stability: The expiration date provided by the manufacturer isrecorded.

E. Storage Conditions: Are provided by the manufacturer.

F. Characteristics: Information on synthesis methods, composition, orother characteristics that define the control article is on file withthe manufacturer.

IX.b4 Experimental Design and Procedures

A. Preparation of mouse cancer cell lines.

HCT-116 cell lines are cultured and prepared according to the ATCCproduct sheet.

B. Establishment of Tumors.

1. 80 female CD-I nude mice (6-7 weeks).

2. Implantation: Cancer cells are injected subcutaneously into rightflank.

For HCT-116 cells: 5×10E6 cells in 50 μL PBS and 50 μL Matrigel in eachfemale CD-1 nude mice.

3. Staging: Once tumors reach approximately 50 mm³ in volume (measuredwith digital caliper), mice are randomized into 7 treatment groups of atleast 10 mice per group based on their tumor volumes. The calculation oftumor volume uses the formula: W×W×L/2.

C. Treatment Regimen.

1. Tumor measurements are recorded three times on Monday, Wednesday andFriday each week.

2. Mouse body weight is recorded once on Monday each week.

3. Daily dose is given by oral gavage, including weekends.

4. The dose is adjusted according to the body weight measurement.

D. Study Group and Dose Levels (Table 5):

TABLE 5 Mice study groups and dosages. Establishment Treatment GroupAnimal ID of Tumors (oral gavage, 10 mL/kg) 1  1 to 10 For 40 mice:Vehicle (s. c injection) 5x10E6 2 41 to 50 HCT-116 cells in 50 μL PBSCompound Example 4 and 50 μL Matrigel 50 mL/kg 3 51 to 60 Mice arerandomized and Compound Example 4 divided into four groups: 100 mL/kg 461 to 70 10 mice/group Compound Example 4 200 mL/kg

E. Monitoring.

1. Record signs of distress daily.

2. Record mouse body weights as described above.

3. Record tumor measurements as described above.

F. Measurements.

-   -   1. Measurements of tumor sizes are continued to the end of this        study.    -   2. Mice are sacrificed at completion of dosing regimen or mice        are sacrificed when tumor size is more than 2000 mm³.

G. Data Collection. At the end of the three-week dosing period, mice aresacrificed, blood, and tumors collected.

IX.b5 Tissue Sample Collections

A. Blood/plasma collection: On Day 7, blood samples are collected fromfirst 3 animals in each group at 90 minutes after dosing andapproximately 50 μL of plasma is obtained and frozen over dry ice.

At the end of the three-week dosing period, blood samples are collectedfrom second 3 animals in each group at 90 minutes after dosing and atminimum 100 uL of plasma is obtained and frozen over dry ice.

B. Tumor collection: The entire tumor is removed, weighed, and recorded.Around 200 mg of tumor from 3 animals in each group are cut, weighed,and frozen over dry ice for PK analysis.

IX.c In Vivo Efficacy Testing Results

The efficacy of treating tumors with 50 mg/kg, 100 mg/kg, and 200 mg/kgdosages of Compound Example 4 was studied and results are shown in FIG.3.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety. While the invention has been disclosed with reference tospecific embodiments, it is apparent that other embodiments andvariations of this invention may be devised by others skilled in the artwithout departing from the true spirit and scope of the invention. Theappended claims are intended to be construed to include all suchembodiments and equivalent variations.

1. (canceled)
 2. (canceled)
 3. A compound of Formula I-B, or a salt orsolvate thereof:

wherein in Formula I-B: Ring A is an aromatic ring having 0-3 ringnitrogen atoms, and wherein Ring A may optionally be substituted by oneor more R^(b)s; Ring B is a saturated or unsaturated 3-7 memberedcarbocyclic ring or a saturated or unsaturated 3-7 membered heterocyclicring having 1-3 ring atoms of O, S, SO, SO₂, or NR^(b), and wherein RingB may optionally be substituted by one or more R^(c)s; R^(a), R^(b) andR^(c) are each independently selected from the group consisting of H, F,Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d) OC(═O)NR^(d)R^(e),CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e),C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from F, Cl, Br, I, CN, NO₂, OR^(d),OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f),CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d),NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), and whereinR^(d), R^(e) and R^(f) are each independently selected from the groupconsisting of H, and optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, and wherein any of R^(d), R^(e) or R^(f) canoptionally be joined to form additional rings; and R^(a), R^(b) andR^(c) can optionally be joined to form additional chain

 is an uninterrupted chain, wherein any bond can be a single, double ortriple bond, consistent with the hybridization state of the connectedatoms, and wherein a null selection for any of the X¹ to X⁷ nodesresults in a null selection for the adjacent R groups; X¹, X², X³, X⁴,X⁵, X⁶, and X⁷ are each independently selected from the group consistingof null, C, CH, CH₂, C(═O), O, N, NH, S, S(═O) and S(═O)₂; R¹, R^(1′),R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′), R⁷ andR^(7′) are each independently selected from the group consisting ofnull, H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶, R^(6′), R⁷ and R^(7′) can optionally be connected to eachother to form various carbocyclic or heterocyclic systems; and Fn isselected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V: R⁸, R^(8′), R⁹, and R¹⁰ are eachindependently selected from the group consisting of null, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ can representsingle, multiple, or no substitution; n is an integer of 0-3.
 4. Acompound having a structure selected from the group consisting ofFormulae VI-A, VII-A, VIII-A, IX-A, X-A, VI-B, VII-B, VIII-B, IX-R, andX-B, or a salt or solvate thereof:

wherein in Formulae VI-A to X-B: R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ are eachindependently selected from the group consisting of H, F, Cl, Br, I, CN,NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e),CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e),C(═O)OR^(d) NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkylis optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein each R^(d), R^(e) and R^(f) isindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ can optionally be joinedto each other to form various carbocyclic or heterocyclic rings; m is aninteger from 0 to 3; q is an integer from 0 to 7; p is an integer from 0to 2; J is selected from the group consisting of CH and N; and Fn isselected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V: R⁸, R^(8′), R⁹, and R¹⁰ are eachindependently selected from the group consisting of null, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ can representsingle, multiple, or no substitution.
 5. The compound of claim 4,wherein the compound has a structure selected from the group consistingof:


6. A method of treating a disease or disorder associated with HDACs in asubject, the method comprising administering to the subject atherapeutically effective amount of a compound of Formula I, Formula I-Aor Formula I-B, or a salt or solvate thereof:

wherein in Formula F Ring A is an aromatic ring having 0-2 ring nitrogenatoms; Ring B is a 3-7 membered saturated or unsaturated carbocyclicring, or a 3-7 membered saturated or unsaturated heterocyclic ringhaving 1-3 ring atoms of O, S, SO, SO₂, or NR³, and wherein Ring B mayoptionally be substituted by one or more R^(b)s; L₁ is a bond or a C₁-C₃alkyl group optionally substituted by R^(b); L₂ is a bond, a C₁-C₃ alkylgroup optionally substituted by R^(b), an alkenyl, or an alkynyl; X isCH₂, O, or NR^(c); each R^(a) and R^(b) is independently selected fromthe group consisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d), OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e),NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f),NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d),S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein each R^(d), R^(e) and R^(f) isindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) may be optionally joined to form additionalrings; and any R^(a) and R^(b) may be optionally joined to formadditional rings; R^(c) is selected from the group consisting of H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I,CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e),CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e),C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), and whereinR^(d), R^(e) and R^(f) are each independently selected from the groupconsisting of H, and optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, and wherein any of R^(d), R^(e) or R^(f) may beoptionally joined to form additional rings; Fn is selected from thegroup consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V: R⁸, R^(8′), R⁹, and R¹⁰ are eachindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl mayoptionally be substituted, and R¹⁰ can represent single, multiple, or nosubstitution; m is an integer from 0-3; and n is an integer from 0-3;

wherein in Formula I-A and Formula I-B: Ring A is an aromatic ringhaving 0-3 ring nitrogen atoms, and wherein Ring A may optionally besubstituted by one or more R^(b)s; Ring B is a saturated or unsaturated3-7 membered carbocyclic ring or a saturated or unsaturated 3-7 memberedheterocyclic ring having 1-3 ring atoms of O, S, SO, SO₂, or NR^(b), andwherein Ring B may optionally be substituted by one or more R^(c)s;R^(a), R^(b) and R^(c) are each independently selected from the groupconsisting of H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d),OC(═O)OR^(d) OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f),C(═O)R^(d), C(═O)NR^(d)R^(e), C(═O)OR^(d) NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and R^(a), R^(b) and R^(c) can optionally be joined to formadditional rings; chain

 is an uninterrupted chain, wherein any bond can be a single, double ortriple bond, consistent with the hybridization state of the connectedatoms, e.g. if X² is an sp hybridized carbon atom and X³ is also an sphybridized carbon atom, then the X²—X³ bond is a triple C—C bond, etc.,wherein a null selection for any of the X¹ to X⁷ nodes will result inconnecting the adjacent nodes, e.g. if X⁵ is null, then X⁴ connects toX⁶, or if X⁴ and X⁵ are both null, then X³ connects with X⁶, etc., andwherein a null selection for any of the X¹ to X⁷ nodes will result in anautomatic null selection for the adjacent R groups, e.g. if X³ is null,then R³ and R^(3′) are both automatically null, etc.; X¹, X², X³, X⁴,X⁵, X⁶, and X⁷ are each independently selected from the group consistingof null, C, CH, CH₂, C(═O), O, N, NH, S, S(═O) and S(═O)₂; R¹, R^(1′),R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′), R⁷ andR^(7′) are each independently selected from the group consisting ofnull, H, F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein R^(d), R^(e) and R^(f) are eachindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶, R^(6′), R⁷ and R^(7′) can optionally be connected to eachother to form various carbocyclic or heterocyclic systems; and Fn isselected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V: R⁸, R^(8′), R⁹, and R¹⁰ are eachindependently selected from the group consisting of null, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ can representsingle, multiple, or no substitution; and n is an integer of 0-3.
 7. Themethod of claim 6, wherein the compound of Formula I-A or I-B is acompound of Formulae VI-A, VII-A, VIII-A, IX-A, X-A, VI-B, VII-B,VIII-B, IX-B, and X-B, or a salt or solvate thereof:

wherein in Formulae VI-A to X-B: R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ are eachindependently selected from the group consisting of H, F, Cl, Br, I, CN,NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d), OC(═O)NR^(d)R^(e),CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d), C(═O)NR^(d)R^(e),C(═O)OR^(d) NR^(d)R^(e), NR^(d)C(═O)R^(e), NR^(d)C(═O)OR^(e),NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e), NR^(d)S(═O)₂NR^(e)R^(f),SR^(d), S(═O)R^(d), S(═O)₂R^(d), and S(═O)₂NR^(d)R^(e), C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkylis optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, I, CN, NO₂, OR^(d), OC(═O)R^(d), OC(═O)OR^(d),OC(═O)NR^(d)R^(e), CR^(d)R^(e)R^(f), CR^(d)R^(e)OR^(f), C(═O)R^(d),C(═O)NR^(d)R^(e), C(═O)OR^(d), NR^(d)R^(e), NR^(d)C(═O)R^(e),NR^(d)C(═O)OR^(e), NR^(d)C(═O)NR^(e)R^(f), NR^(d)S(═O)₂R^(e),NR^(d)S(═O)₂NR^(e)R^(f), SR^(d), S(═O)R^(d), S(═O)₂R^(d), andS(═O)₂NR^(d)R^(e), and wherein each R^(d), R^(e) and R^(f) isindependently selected from the group consisting of H, and optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and whereinany of R^(d), R^(e) or R^(f) can optionally be joined to form additionalrings; and any of R¹¹, R¹², R¹³, R¹⁴, and R¹⁴ can optionally be joinedto each other to form various carbocyclic or heterocyclic rings; m is aninteger from 0 to 3; q is an integer from 0 to 7; p is an integer from 0to 2; J is selected from the group consisting of CH and N; and Fn isselected from the group consisting of Formulae II, III, IV and V:

wherein in Formulae II, III, IV and V: R⁸, R^(8′), R⁹, and R¹⁰ are eachindependently selected from the group consisting of null, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, and R¹⁰ can representsingle, multiple, or no substitution.
 8. The method of claim 6, whereinthe compound of Formula I is selected from the group consisting of


9. The method of claim 7, wherein the compound of Formulae VI-A, VII-A,VIII-A, IX-A, X-A, VI-B, VII-B, VIII-B, IX-B, or X-B is selected fromthe group consisting of:


10. The method of claim 6, wherein the compound selectively inhibitsHDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10,HDAC11, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7, andcombinations thereof.
 11. The method of claim 6, wherein the compoundselectively inhibits HDAC
 6. 12. The method of claim 6, wherein thecompound selectively inhibits HDAC
 8. 13. The method of claim 6, whereinthe disease or disorder is selected from the group consisting of cancer,a psychiatric disease or disorder, a neurologic disease or disorder, aneurodegenerative disease or disorder, and a neuroinflammation diseaseor disorder.
 14. The method of claim 6, further comprising:administering to the subject a therapeutically effective amount of anadditional therapeutic agent for the treatment of a disease or disorderwherein the additional therapeutic agent is selected from the groupconsisting of an immunomodulatory drug, an immunotherapeutic drug, aDNA-damaging chemotherapeutic, a proteasome inhibitor, an anti-androgenreceptor, an antiretroviral drug, a reverse-transcriptase inhibitor, achemotherapeutic drug, and an immunosuppressant.
 15. A method ofimmunomodulation for organ transplant, the method comprisingadministering to a patient a therapeutically effective amount of acompound of claim
 4. 16. A kit for inhibiting an HDAC or for treating adisease or disorder associated with an HDAC in a subject, comprising anamount of a compound of claim 4, or a salt or solvate thereof, and aninstruction manual for the use thereof.
 17. A probe for imaging,diagnosing, or theragnosting a disease or disorder associated with anHDAC in a subject, comprising a compound of claim 4, or a salt orsolvate thereof.
 18. A method of immunomodulation for organ transplant,the method comprising administering to a patient a therapeuticallyeffective amount of a compound of claim
 3. 19. A kit for inhibiting anHDAC or for treating a disease or disorder associated with an HDAC in asubject, comprising an amount of a compound of claim 3, or a salt orsolvate thereof, and an instruction manual for the use thereof.
 20. Aprobe for imaging, diagnosing, or theragnosting a disease or disorderassociated with an HDAC in a subject, comprising a compound of claim 3,or a salt or solvate thereof.